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Macronutrients and the Adipose-Liver Axis in Obesity and Fatty Liver

  • Caroline C. Duwaerts
    Correspondence
    Correspondence Address correspondence to: Caroline C. Duwaerts, PhD, Liver Center Laboratory, 513 Parnassus Avenue, Health Sciences East, 1401, San Francisco, California 94143. fax: +1 4155140235.
    Affiliations
    Department of Medicine and Liver Center, University of California, San Francisco, San Francisco, California
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  • Jacquelyn J. Maher
    Affiliations
    Department of Medicine and Liver Center, University of California, San Francisco, San Francisco, California
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Open AccessPublished:February 11, 2019DOI:https://doi.org/10.1016/j.jcmgh.2019.02.001
      Macronutrient metabolism is a highly orchestrated process, with adipose tissue and liver each playing central roles in nutrient uptake, processing, transport, and storage. These 2 tissues form an important metabolic circuit, particularly as it relates to lipids as the primary storage form of excess energy. The function of the circuit is influenced by many factors, including the quantity and type of nutrients consumed and their impact on the overall health of the tissues. In this review we begin with a brief summary of the homeostatic disposition of lipids between adipose tissue and liver and how these processes can become dysregulated in obesity. We then explore how specific dietary nutrients and nutrient combinations can exert unique influences on the liver–adipose tissue axis.

      Keywords

      Abbreviations used in this paper:

      DNL (de novo lipogenesis), ER (endoplasmic reticulum), FFA (free fatty acid), FGF21 (fibroblast growth factor-21), LPL (lipoprotein lipase), MUFA (monounsaturated fatty acid), NAFLD (nonalcoholic fatty liver disease), PUFA (polyunsaturated fatty acid), SFA (saturated fatty acid), VLDL (very-low-density lipoprotein)
      The present review addresses the complex role of carbohydrates (simple and complex) and fats (saturated, unsaturated, polyunsaturated) in the pathogenesis of nonalcoholic fatty liver disease. Specifically the review focuses on the liver–adipose tissue axis in this disease and the role each nutrient class plays in the crosstalk between the liver and the adipose tissue and the pathophysiology of nonalcoholic fatty liver disease.

      Macronutrient Flux Through Adipose Tissue and Liver

      When a healthy individual consumes dietary fat, the lipids are converted to triglyceride within the intestine and packaged into chylomicrons for delivery to peripheral tissues (primarily muscle and adipose tissue) (Figure 1). When chylomicrons reach their target tissues, fatty acids are released through the local action of lipoprotein lipase (LPL). Adipose tissue is reasonably efficient at extracting free fatty acids (FFA) from chylomicrons for uptake and storage; however, there is some “spillover” of FFA into the circulation (33%–36% of the total delivered), which then become available for uptake by the liver.
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      The chylomicron remnants that are left after LPL-mediated triglyceride lipolysis also contain a small proportion of their original triglyceride content. Spillover FFA and chylomicron remnants represent 2 routes by which dietary fat can gain direct access to the liver. Stable isotope studies indicate that in normal individuals, dietary fat accounts for approximately 15% of the triglyceride present in the liver at any given time.
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      Figure thumbnail gr1
      Figure 1Route of dietary carbohydrates and fats to the liver and adipose tissue. Dietary carbohydrate enters the portal circulation from the intestine and enters the liver. Excess substrate not needed for metabolism is converted to fatty acid via DNL and incorporated into triglyceride. Triglycerides are exported from the liver as VLDL, where they are delivered to adipose tissue, where they are broken down into FFA by the enzyme LPL and stored. Dietary fat is packaged into chylomicrons in the intestine and delivered initially to muscle and adipose tissue. Any lipid remaining in the chylomicron remnants are routed to the liver, as are “spillover” FFA not taken up by adipocytes. CHO, carbohydrate; TG, triglyceride.
      When a healthy individual consumes carbohydrate, any substrate in excess of that needed to fulfill short-term metabolic need is converted into fatty acid through de novo lipogenesis (DNL). DNL takes place in both the liver and adipose tissue (reviewed in
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      ). The fatty acid products of DNL are esterified into triglyceride for storage; the primary reservoir for stored lipids is in adipose tissue, and thus the triglyceride produced in adipose tissue is stored directly. In the liver, some newly synthesized triglyceride is stored locally, but most is packaged into very low density lipoproteins (VLDL) for export to adipose tissue.
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      Adipose tissue extracts lipid from VLDL in the same fashion as it does from chylomicrons, using LPL. When carbohydrates and lipids are consumed simultaneously, adipose tissue is called on to import glucose for DNL and take up lipids from both chylomicrons and VLDL. Insulin, induced by dietary carbohydrate, helps adipose tissue accommodate the substrate load by increasing cell-surface expression of the GLUT4 glucose transporter
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      and increasing adipose tissue LPL activity.
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      During fasting, adipose tissue becomes a net exporter rather than importer of lipid. When nutrients and insulin are sparse, adipocytes hydrolyze their intracellular triglycerides using hormone-sensitive lipase and release FFA for uptake by several tissues including the liver. Indeed, 59% of the triglyceride in a normal liver derives from FFA taken up from the circulation.
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      • Parks E.J.
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      In obesity, the situation in adipose tissue resembles fasting: although insulin levels are adequate or even high, adipocytes can no longer respond to the anabolic effects of the hormone, so they instead behave as though they are insulin-deficient, hydrolyzing intracellular triglyceride and releasing FFA into the circulation. To make matters worse, insulin resistance also suppresses the ability of adipocytes to take up lipid from chylomicrons and VLDL. This leads to further increases in circulating FFA, which are then diverted to other tissues including the liver, where they are stored as ectopic lipid. Overall, alterations in nutrient flux through the adipose-liver circuit play a key role in the pathogenesis of fatty liver disease. Dietary carbohydrates exert a direct influence on the liver through DNL; carbohydrates and fats can also contribute indirectly to fatty liver by increasing adipose tissue lipid stores that are subsequently mobilized through lipolysis.
      The adipose tissue–liver metabolic circuit is sensitive not only to the total amount of calories consumed but also the distribution of calories across macronutrient classes (carbohydrates and fats) and even to individual types of macronutrients. The following sections explore the impact of specific nutrients and nutrient combinations on adipose tissue and liver health.

      The Influence of Obesity on the Adipose-Liver Axis

      Under normal physiological conditions the liver and adipose tissue strive to maintain metabolic homeostasis through the secretion of adipokines and growth factors.
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      Under conditions of nutrient excess this communication is disrupted, contributing to metabolic derangement and related injury to both organs.
      Looking first at adipose tissue, obesity prompts an increase in tissue mass through a combination of adipocyte hypertrophy and hyperplasia. This enlargement increases oxygen consumption and strains oxygen delivery to the tissue,
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      Diseased adipocytes also undergo changes in adipokine production: for example, adiponectin, which promotes physiological lipid storage in fat and lipid oxidation in muscle and liver, is significantly decreased in obesity.
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      In contrast, inflammatory cytokines and chemokines, such as tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1 (CCL2), and others, are produced in increased amounts by adipocytes (reviewed in
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      This interferes with the ability of adipocytes to take up fatty acids from the circulation, and furthermore induces the hydrolysis of intracellular triglycerides, which leads to the systemic release of more fatty acids. Cytokines also promote the recruitment of inflammatory cells to adipose tissue, which inflict further damage, thus perpetuating adipose tissue dysfunction.
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      Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
      Overall, the dysregulation of metabolic and immunoregulatory adipokines in dysfunctional adipose tissue results in the rerouting of fatty acids to other “ectopic” tissues, including the liver.
      The principal compound secreted by the liver that influences the adipose-liver axis is fibroblast growth factor-21 (FGF21). FGF21, produced by hepatocytes, promotes glucose uptake and energy expenditure in white adipose tissue.
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      In response to FGF21, adipose tissue secretes adiponectin, which then circles back to the liver to facilitate insulin signaling.
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      In obesity, hepatic production of FGF21 is upregulated.
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      Its action toward white adipose tissue, however, is blunted.
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      underscoring how obesity interferes with another fundamental circuit intended to maintain metabolic homeostasis.

      The Influence of Specific Dietary Macronutrients on the Liver and Adipose Tissue

      It is well established that consumption of excess calories is a major factor in the development of obesity and fatty liver disease, particularly when coupled with genetic predispositions and a sedentary lifestyle. There is also information indicating that the composition of a diet, independent of its caloric content, can exert a unique influence on the well-being and function of adipose tissue and liver. In this section we highlight the role of macronutrients in nonalcoholic fatty liver disease (NAFLD) pathogenesis, paying particular attention to their effect on adipose-liver interactions. The discussion is organized by macronutrient class, specifically highlighting carbohydrates and fats. Although we focus on macronutrients 1 group at a time, it is important to keep in mind that the human diet constitutes a mixture of carbohydrates, fats, and proteins. The standard human diet comprises 40%–50% carbohydrate, 30%–40% fat, and 20% protein. The interactions among macronutrient classes can themselves be biologically important, and we highlight these in select cases.

      Dietary Carbohydrates

      Carbohydrates are designated as simple or complex based on the number of sugar molecules they contain (monosaccharides and disaccharides vs polysaccharides). Individual carbohydrates differ in their abilities to induce DNL,
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      which plays a role in their tendency to provoke fatty liver and more serious forms of liver injury. Numerous studies have investigated the role of dietary carbohydrates in NAFLD pathogenesis. Less information is available on the role of dietary carbohydrates on adipose tissue in the context of NAFLD.

      Simple Carbohydrates

      Simple carbohydrates (sugars) include the dietary sweeteners glucose, fructose, and sucrose. Glucose and fructose are monosaccharides, whereas sucrose is a disaccharide comprised of glucose and fructose. Glucose and fructose are readily absorbed by the small intestine. Until recently, both molecules were believed to be transported directly from the intestine to the portal circulation for delivery to the liver; however, new evidence indicates that fructose is metabolized by the intestine and enters the portal circulation only when consumed in amounts sufficient to saturate this metabolic capacity.
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      • Fitzgerald K.
      • Ilkayeva O.
      • Newgard C.B.
      • Cohen D.E.
      • Kahn C.R.
      Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.
      This acts as an ongoing stimulus to lipolysis in fructose-exposed adipose tissue. Moreover, the uric acid produced during fructose metabolism can inflict damage on adipocytes, stimulating oxidant stress and the production of inflammatory cytokines.
      • Baldwin W.
      • McRae S.
      • Marek G.
      • Wymer D.
      • Pannu V.
      • Baylis C.
      • Johnson R.J.
      • Sautin Y.Y.
      Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome.
      • Sautin Y.Y.
      • Nakagawa T.
      • Zharikov S.
      • Johnson R.J.
      Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress.
      Overall, the adverse effects of fructose on adipocytes compound its adverse effects on the liver, by causing adipose inflammation and preventing proper adipose tissue lipid storage resulting in diversion of fatty acids to the liver (Figure 2).
      Figure thumbnail gr2
      Figure 2Endocrine interactions between liver and adipose tissue and the influence of macronutrients. Under conditions of dietary excess/obesity, adipose tissue adiponectin production declines and several proinflammatory cytokines and chemokines are upregulated. This can promote inflammation and insulin resistance in both tissues. FGF21 is upregulated in the liver, but its action is inhibited, preventing energy expenditure in adipose tissue and promoting lipolysis. The general contribution of individual macronutrients to the dysfunction of adipose tissue and liver in obesity and NAFLD is shown schematically (see text for details). CHO, carbohydrate; IL, interleukin; TNF, tumor necrosis factor.
      The effects of glucose on liver and adipose tissue are generally milder than fructose, although overconsumption of glucose is not without consequence. Like fructose, glucose promotes DNL, which yields SFAs that are esterified and stored in adipose tissue and liver. Studies in mice indicate that glucose and fructose induce similar degrees of hepatic lipid accumulation when incorporated into isocaloric diets.
      • Pickens M.K.
      • Ogata H.
      • Soon R.K.
      • Grenert J.P.
      • Maher J.J.
      Dietary fructose exacerbates hepatocellular injury when incorporated into a methionine-choline-deficient diet.
      • Softic S.
      • Gupta M.K.
      • Wang G.X.
      • Fujisaka S.
      • O'Neill B.T.
      • Rao T.N.
      • Willoughby J.
      • Harbison C.
      • Fitzgerald K.
      • Ilkayeva O.
      • Newgard C.B.
      • Cohen D.E.
      • Kahn C.R.
      Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.
      Similarly in humans, when identical amounts of glucose or fructose are fed to human subjects for periods up to 4 weeks, both sugars induce comparable increases in liver fat content.
      • Johnston R.D.
      • Stephenson M.C.
      • Crossland H.
      • Cordon S.M.
      • Palcidi E.
      • Cox E.F.
      • Taylor M.A.
      • Aithal G.P.
      • Macdonald I.A.
      No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men.
      • Ngo Sock E.T.
      • Le K.A.
      • Ith M.
      • Kreis R.
      • Boesch C.
      • Tappy L.
      Effects of a short-term overfeeding with fructose or glucose in healthy young males.
      • Silbernagel G.
      • Machann J.
      • Unmuth S.
      • Schick F.
      • Stefan N.
      • Haring H.U.
      • Fritsche A.
      Effects of 4-week very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: an exploratory trial.
      Because the lipogenic properties of glucose and fructose seem similar, the increased harm from fructose in humans is likely related to ATP depletion and uric acid production and their downstream consequences.
      One important point to note about dietary sugars is that their ability to induce liver injury is modulated by the fat present in the diet. Specifically, saturated fat induces DNL independently of dietary sugar,
      • Lin J.
      • Yang R.
      • Tarr P.T.
      • Wu P.H.
      • Handschin C.
      • Li S.
      • Yang W.
      • Pei L.
      • Uldry M.
      • Tontonoz P.
      • Newgard C.B.
      • Spiegelman B.M.
      Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP.
      so when sugar and saturated fat are consumed together, the DNL effect is magnified. This synergy is most evident when sugar (as the DNL substrate) is highly abundant in the diet. Our group showed that sugar + saturated fat, when fed to mice in a ratio of 60:20, induced significantly more DNL, hepatic steatosis, and liver injury than an equivalent combination of sugar + unsaturated fat.
      • Pierce A.A.
      • Pickens M.K.
      • Siao K.
      • Grenert J.P.
      • Maher J.J.
      Differential hepatotoxicity of dietary and DNL-derived palmitate in the methionine-choline-deficient model of steatohepatitis.
      • Pierce A.A.
      • Duwaerts C.C.
      • Soon R.K.
      • Siao K.
      • Grenert J.P.
      • Fitch M.
      • Hellerstein M.K.
      • Beysen C.
      • Turner S.M.
      • Maher J.J.
      Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury.
      This synergy was not seen when sugar + saturated fat were fed in a ratio of 40:40.
      • Duwaerts C.C.
      • Amin A.M.
      • Siao K.
      • Her C.
      • Fitch M.
      • Beysen C.
      • Turner S.M.
      • Goodsell A.
      • Baron J.L.
      • Grenert J.P.
      • Cho S.J.
      • Maher J.J.
      Specific macronutrients exert unique influences on the adipose-liver axis to promote hepatic steatosis in mice.

      Complex Carbohydrates

      Complex carbohydrates (starches, glucans, fructans, and cellulose) are polysaccharides with a range of structures and physical properties. Glucans, fructans, and cellulose, along with a subset of starches that are highly resistant to enzymatic digestion, are often grouped into a single category under the term “dietary fiber.” The impact of starches and fiber on adipose tissue and liver is dependent in part on their metabolism by the host, but also on their metabolism by microbes residing in the gut.

      Starches

      Starches are polymers of glucose with different chain lengths and α-glycosidic linkages. Like all polysaccharides, they require enzymatic digestion before absorption. However, because of their size and structure they are not completely degraded to monosaccharides or disaccharides in the small intestine and as a result are less “glycemic” than simple sugars. Because starch yields lower blood concentrations of glucose than sugar, it is less likely to stimulate lipogenic genes in the liver; furthermore, it provides less substrate for fatty acid synthesis. The blunted lipogenic effect of dietary starch compared with sugar has been demonstrated in direct comparisons of the 2 carbohydrates in mice.
      • Pickens M.K.
      • Yan J.S.
      • Ng R.K.
      • Ogata H.
      • Grenert J.P.
      • Beysen C.
      • Turner S.M.
      • Maher J.J.
      Dietary sucrose is essential to the development of liver injury in the methionine-choline-deficient model of steatohepatitis.
      Even within the category of dietary starches there are variations in the ability of individual polysaccharides to stimulate hepatic lipogenesis depending on the ease with which they are digested.
      • Scribner K.B.
      • Pawlak D.B.
      • Ludwig D.S.
      Hepatic steatosis and increased adiposity in mice consuming rapidly vs. slowly absorbed carbohydrate.
      The impact of high-glycemic (digestible) and low-glycemic (resistant) starches on adipose tissue have also been investigated in select studies.
      • Coate K.C.
      • Huggins K.W.
      Consumption of a high glycemic index diet increases abdominal adiposity but does not influence adipose tissue pro-oxidant and antioxidant gene expression in C57BL/6 mice.
      • Lerer-Metzger M.
      • Rizkalla S.W.
      • Luo J.
      • Champ M.
      • Kabir M.
      • Bruzzo F.
      • Bornet F.
      • Slama G.
      Effects of long-term low-glycaemic index starchy food on plasma glucose and lipid concentrations and adipose tissue cellularity in normal and diabetic rats.
      As expected, high-glycemic starches induced more adipose tissue enlargement than low-glycemic starches. At present there is little information available about the effect of dietary starches on adipose tissue inflammation.

      Fiber

      Fiber is either very resistant to enzymatic digestion in the intestine, or in the case of β-linked plant polysaccharides (β-glucans and cellulose), cannot be digested at all by the intestine. These resistant polysaccharides make their way to the colon, where they undergo fermentation by colonic bacteria.
      • Flint H.J.
      • Scott K.P.
      • Duncan S.H.
      • Louis P.
      • Forano E.
      Microbial degradation of complex carbohydrates in the gut.
      Fermentation of fiber yields the short-chain fatty acids acetate, butyrate and propionate; some of these are used by the bacteria themselves, but some are also absorbed into the portal circulation where they have immediate access to the liver.
      • Bach Knudsen K.E.
      Microbial degradation of whole-grain complex carbohydrates and impact on short-chain fatty acids and health.
      Hepatic extraction of short-chain fatty acids is efficient but incomplete. This enables some fatty acids to enter the systemic circulation
      • Boets E.
      • Gomand S.V.
      • Deroover L.
      • Preston T.
      • Vermeulen K.
      • De Preter V.
      • Hamer H.M.
      • Van den Mooter G.
      • De Vuyst L.
      • Courtin C.M.
      • Annaert P.
      • Delcour J.A.
      • Verbeke K.A.
      Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study.
      where they can exert independent influences on adipose tissue. Focusing on the liver first, it is important to note that short-chain fatty acids have several effects on hepatic metabolism that can either promote or prevent NAFLD. Butyrate stimulates fatty acid oxidation and thus should be beneficial to the liver.
      • Gao Z.
      • Yin J.
      • Zhang J.
      • Ward R.E.
      • Martin R.J.
      • Lefevre M.
      • Cefalu W.T.
      • Ye J.
      Butyrate improves insulin sensitivity and increases energy expenditure in mice.
      In contrast, acetate is a substrate for hepatic lipogenesis
      • den Besten G.
      • Lange K.
      • Havinga R.
      • van Dijk T.H.
      • Gerding A.
      • van Eunen K.
      • Muller M.
      • Groen A.K.
      • Hooiveld G.J.
      • Bakker B.M.
      • Reijngoud D.J.
      Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids.
      and propionate stimulates gluconeogenesis,
      • Perry R.J.
      • Borders C.B.
      • Cline G.W.
      • Zhang X.M.
      • Alves T.C.
      • Petersen K.F.
      • Rothman D.L.
      • Kibbey R.G.
      • Shulman G.I.
      Propionate increases hepatic pyruvate cycling and anaplerosis and alters mitochondrial metabolism.
      which should have an overall adverse effect. A recent mouse study disputes the prospect of harm by demonstrating that supplemental short-chain fatty acids prevent, rather than promote, experimental fatty liver disease.
      • Weitkunat K.
      • Stuhlmann C.
      • Postel A.
      • Rumberger S.
      • Fankhanel M.
      • Woting A.
      • Petzke K.J.
      • Gohlke S.
      • Schulz T.J.
      • Blaut M.
      • Klaus S.
      • Schumann S.
      Short-chain fatty acids and inulin, but not guar gum, prevent diet-induced obesity and insulin resistance through differential mechanisms in mice.
      Overall it remains unclear whether the net effect of short-chain fatty acids on the liver is beneficial or detrimental in the pathogenesis of NAFLD, although experts are leaning toward a salutary role for these compounds.
      • Chu H.
      • Duan Y.
      • Yang L.
      • Schnabl B.
      Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease.
      With respect to adipose tissue, short-chain fatty acids are believed beneficial to metabolic homeostasis. Animals and cell culture studies demonstrate that short-chain fatty acids promote adipocyte development and fat accumulation, stimulate adipokine production, and decrease lipolysis.
      • Ferchaud-Roucher V.
      • Pouteau E.
      • Piloquet H.
      • Zair Y.
      • Krempf M.
      Colonic fermentation from lactulose inhibits lipolysis in overweight subjects.
      • Hong Y.H.
      • Nishimura Y.
      • Hishikawa D.
      • Tsuzuki H.
      • Miyahara H.
      • Gotoh C.
      • Choi K.C.
      • Feng D.D.
      • Chen C.
      • Lee H.G.
      • Katoh K.
      • Roh S.G.
      • Sasaki S.
      Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43.
      • Lee S.H.
      • Hossner K.L.
      Coordinate regulation of ovine adipose tissue gene expression by propionate.
      • Xiong Y.
      • Miyamoto N.
      • Shibata K.
      • Valasek M.A.
      • Motoike T.
      • Kedzierski R.M.
      • Yanagisawa M.
      Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41.
      Human studies, although correlative, indicate that diets that increase circulating levels of short-chain fatty acids also reduce systemic circulating fatty acid concentrations, suggesting a suppressive effect on adipose tissue lipolysis.
      • Robertson M.D.
      • Bickerton A.S.
      • Dennis A.L.
      • Vidal H.
      • Frayn K.N.
      Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism.

      Dietary Fats

      Dietary fats are consumed largely as triglycerides. Fats are named for the dominant type of fatty acid within the triglyceride molecule: SFAs, monounsaturated fatty acids (MUFA) or polyunsaturated fatty acids (PUFA). Dietary fat is taken up by tissues in the form of fatty acids after lipolysis of triglycerides at the cell surface. Fats are primarily incorporated into adipose tissue; they have secondary access to the liver via chylomicron remnants or spillover of excess FFAs into the circulation (Figure 1). The biologic effects of dietary fats are attributable to their component fatty acids, which are the main focus of the following summary.

      Saturated Fats

      Saturated fats and their component SFA come primarily from animal sources (meat and dairy). The SFA present in these foods are typically long-chain species containing 16 or more carbon atoms. Long-chain SFA are considered the most harmful of dietary fats because they have toxic effects on many types of cells; this is in contrast to medium-chain SFA, which are more inert and can even be beneficial to metabolic health.
      • Lee J.Y.
      • Zhao L.
      • Youn H.S.
      • Weatherill A.R.
      • Tapping R.
      • Feng L.
      • Lee W.H.
      • Fitzgerald K.A.
      • Hwang D.H.
      Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1.
      • Bhavsar N.
      • St-Onge M.P.
      The diverse nature of saturated fats and the case of medium-chain triglycerides: how one recommendation may not fit all.
      Although medium-chain SFA are less toxic than long-chain SFA they are only minor components of standard meat and dairy items. However, they are enriched in a limited number of natural foods, such as coconut and palm kernel oils. Focusing on long-chain SFA because of their prevalence in the standard human diet, these SFA can directly injure hepatocytes through a variety of mechanisms including death receptor signaling, the induction of ER stress leading to intrinsic mitochondrial apoptosis, stimulation of toll-like receptors, activation of inflammasomes, and impairment of autophagy (reviewed in
      • Hirsova P.
      • Ibrahim S.H.
      • Gores G.J.
      • Malhi H.
      Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis.
      ).
      • Barreyro F.J.
      • Kobayashi S.
      • Bronk S.F.
      • Werneburg N.W.
      • Malhi H.
      • Gores G.J.
      Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis.
      • Cazanave S.C.
      • Mott J.L.
      • Bronk S.F.
      • Werneburg N.W.
      • Fingas C.D.
      • Meng X.W.
      • Finnberg N.
      • El-Deiry W.S.
      • Kaufmann S.H.
      • Gores G.J.
      Death receptor 5 signaling promotes hepatocyte lipoapoptosis.
      • Cazanave S.C.
      • Mott J.L.
      • Elmi N.A.
      • Bronk S.F.
      • Werneburg N.W.
      • Akazawa Y.
      • Kahraman A.
      • Garrison S.P.
      • Zambetti G.P.
      • Charlton M.R.
      • Gores G.J.
      JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis.
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      • Holzer R.G.
      • Park E.J.
      • Li N.
      • Tran H.
      • Chen M.
      • Choi C.
      • Solinas G.
      • Karin M.
      Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation.
      • Malhi H.
      • Bronk S.F.
      • Werneburg N.W.
      • Gores G.J.
      Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.
      • Pfaffenbach K.T.
      • Gentile C.L.
      • Nivala A.M.
      • Wang D.
      • Wei Y.
      • Pagliassotti M.J.
      Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death.
      • Sharma M.
      • Urano F.
      • Jaeschke A.
      Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes.
      • Singh R.
      • Kaushik S.
      • Wang Y.
      • Xiang Y.
      • Novak I.
      • Komatsu M.
      • Tanaka K.
      • Cuervo A.M.
      • Czaja M.J.
      Autophagy regulates lipid metabolism.
      • Wei Y.
      • Wang D.
      • Topczewski F.
      • Pagliassotti M.J.
      Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.
      SFA are also detrimental to adipocytes. They enhance adipocyte oxygen consumption, which contributes to adipose tissue hypoxia in vivo,
      • Trayhurn P.
      Hypoxia and adipose tissue function and dysfunction in obesity.
      • Lee Y.S.
      • Kim J.W.
      • Osborne O.
      • Oh D.Y.
      • Sasik R.
      • Schenk S.
      • Chen A.
      • Chung H.
      • Murphy A.
      • Watkins S.M.
      • Quehenberger O.
      • Johnson R.S.
      • Olefsky J.M.
      Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity.
      • Pasarica M.
      • Sereda O.R.
      • Redman L.M.
      • Albarado D.C.
      • Hymel D.T.
      • Roan L.E.
      • Rood J.C.
      • Burk D.H.
      • Smith S.R.
      Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response.
      and in similar fashion to hepatocytes they cause ER stress, activation of toll-like receptor and nuclear factor-κB, which results in cell death and the production of proinflammatory cytokines.
      • Ajuwon K.M.
      • Spurlock M.E.
      Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes.
      • Bradley R.L.
      • Fisher F.F.
      • Maratos-Flier E.
      Dietary fatty acids differentially regulate production of TNF-alpha and IL-10 by murine 3T3-L1 adipocytes.
      • Davis J.E.
      • Gabler N.K.
      • Walker-Daniels J.
      • Spurlock M.E.
      The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes.
      • Guo W.
      • Wong S.
      • Xie W.
      • Lei T.
      • Luo Z.
      Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes.
      • Hunnicutt J.W.
      • Hardy R.W.
      • Williford J.
      • McDonald J.M.
      Saturated fatty acid-induced insulin resistance in rat adipocytes.
      • Yeop Han C.
      • Kargi A.Y.
      • Omer M.
      • Chan C.K.
      • Wabitsch M.
      • O'Brien K.D.
      • Wight T.N.
      • Chait A.
      Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation.
      • Youssef-Elabd E.M.
      • McGee K.C.
      • Tripathi G.
      • Aldaghri N.
      • Abdalla M.S.
      • Sharada H.M.
      • Ashour E.
      • Amin A.I.
      • Ceriello A.
      • O'Hare J.P.
      • Kumar S.
      • McTernan P.G.
      • Harte A.L.
      Acute and chronic saturated fatty acid treatment as a key instigator of the TLR-mediated inflammatory response in human adipose tissue, in vitro.
      • Schaeffler A.
      • Gross P.
      • Buettner R.
      • Bollheimer C.
      • Buechler C.
      • Neumeier M.
      • Kopp A.
      • Schoelmerich J.
      • Falk W.
      Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity.
      The adverse effects of SFA-enriched diets on liver and adipose tissue have been documented in many studies in experimental animals.
      • Gentile C.L.
      • Weir T.L.
      • Cox-York K.A.
      • Wei Y.
      • Wang D.
      • Reese L.
      • Moran G.
      • Estrada A.
      • Mulligan C.
      • Pagliassotti M.J.
      • Foster M.T.
      The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD.
      • Singh R.
      • Wang Y.
      • Xiang Y.
      • Tanaka K.E.
      • Gaarde W.A.
      • Czaja M.J.
      Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance.
      • Svegliati-Baroni G.
      • Candelaresi C.
      • Saccomanno S.
      • Ferretti G.
      • Bachetti T.
      • Marzioni M.
      • De Minicis S.
      • Nobili L.
      • Salzano R.
      • Omenetti A.
      • Pacetti D.
      • Sigmund S.
      • Benedetti A.
      • Casini A.
      A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury.
      • Lee Y.S.
      • Kim J.W.
      • Osborne O.
      • Oh D.Y.
      • Sasik R.
      • Schenk S.
      • Chen A.
      • Chung H.
      • Murphy A.
      • Watkins S.M.
      • Quehenberger O.
      • Johnson R.S.
      • Olefsky J.M.
      Increased adipocyte O2 consumption triggers HIF-1alpha, causing inflammation and insulin resistance in obesity.
      • Wei Y.
      • Wang D.
      • Topczewski F.
      • Pagliassotti M.J.
      Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.
      • Enos R.T.
      • Velazquez K.T.
      • Murphy E.A.
      Insight into the impact of dietary saturated fat on tissue-specific cellular processes underlying obesity-related diseases.
      • Finucane O.M.
      • Lyons C.L.
      • Murphy A.M.
      • Reynolds C.M.
      • Klinger R.
      • Healy N.P.
      • Cooke A.A.
      • Coll R.C.
      • McAllan L.
      • Nilaweera K.N.
      • O'Reilly M.E.
      • Tierney A.C.
      • Morine M.J.
      • Alcala-Diaz J.F.
      • Lopez-Miranda J.
      • O'Connor D.P.
      • O'Neill L.A.
      • McGillicuddy F.C.
      • Roche H.M.
      Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1beta secretion and insulin resistance despite obesity.
      In contrast, relatively few research groups have challenged human subjects with saturated-fat diets in the context of a controlled clinical trial. The available data from short-term human studies comparing dietary saturated fats with polyunsaturated fats indicate that saturated fats have a greater tendency to induce insulin resistance, hepatic steatosis, and a proinflammatory state characterized by elevated serum concentrations of tumor necrosis factor and interleukin-1-receptor antagonist.
      • Bjermo H.
      • Iggman D.
      • Kullberg J.
      • Dahlman I.
      • Johansson L.
      • Persson L.
      • Berglund J.
      • Pulkki K.
      • Basu S.
      • Uusitupa M.
      • Rudling M.
      • Arner P.
      • Cederholm T.
      • Ahlstrom H.
      • Riserus U.
      Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial.
      • de Wit N.
      • Derrien M.
      • Bosch-Vermeulen H.
      • Oosterink E.
      • Keshtkar S.
      • Duval C.
      • de Vogel-van den Bosch J.
      • Kleerebezem M.
      • Muller M.
      • van der Meer R.
      Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine.
      • Rosqvist F.
      • Iggman D.
      • Kullberg J.
      • Cedernaes J.
      • Johansson H.E.
      • Larsson A.
      • Johansson L.
      • Ahlstrom H.
      • Arner P.
      • Dahlman I.
      • Riserus U.
      Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans.
      • Summers L.K.
      • Fielding B.A.
      • Bradshaw H.A.
      • Ilic V.
      • Beysen C.
      • Clark M.L.
      • Moore N.R.
      • Frayn K.N.
      Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity.
      Although there is little doubt that SFA are cytotoxic, the toxicity of SFA toward liver cells in vivo seems dependent on their origin from the diet or DNL. This observation comes from studies from our laboratory investigating the hepatotoxicity of different combinations of dietary sugars and fats in mice. We reported that dietary tripalmitin, despite being comprised exclusively of SFA, caused only mild liver injury unless paired with sucrose.
      • Pierce A.A.
      • Pickens M.K.
      • Siao K.
      • Grenert J.P.
      • Maher J.J.
      Differential hepatotoxicity of dietary and DNL-derived palmitate in the methionine-choline-deficient model of steatohepatitis.
      This suggests that DNL SFA are more toxic than dietary SFA, which corroborates evidence in humans that fatty liver disease is related to excessive DNL.
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      • Lambert J.E.
      • Ramos-Roman M.A.
      • Browning J.D.
      • Parks E.J.
      Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.

      Unsaturated Fats

      Unsaturated fats, which comprise MUFA and PUFA species, are the principal fats present in plants, seeds, nuts, and fish. The dominant dietary MUFA is oleic acid, which is abundant in olive oil. The dominant dietary PUFAs are linoleic acid (ω-6 PUFA) and α-linolenic acid (ω-3 PUFA) found in seeds and vegetables; other important dietary ω-3 PUFAs are the very long chain species eicosapentaenoic acid and docosahexaenoic acid, which can be produced from α-linolenic acid or obtained directly from a diet containing fish.
      • Scorletti E.
      • Byrne C.D.
      Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.
      In general, unsaturated fats are considered healthier than saturated fats for the liver and adipose tissue. Still, there are properties that distinguish MUFA from PUFA, so the 2 classes are summarized individually.

      Monounsaturated Fatty Acid

      MUFA, unlike SFA, exert little toxicity toward liver or adipose tissue cells.
      • Malhi H.
      • Bronk S.F.
      • Werneburg N.W.
      • Gores G.J.
      Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.
      • Wei Y.
      • Wang D.
      • Topczewski F.
      • Pagliassotti M.J.
      Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.
      • Bradley R.L.
      • Fisher F.F.
      • Maratos-Flier E.
      Dietary fatty acids differentially regulate production of TNF-alpha and IL-10 by murine 3T3-L1 adipocytes.
      • Schaeffler A.
      • Gross P.
      • Buettner R.
      • Bollheimer C.
      • Buechler C.
      • Neumeier M.
      • Kopp A.
      • Schoelmerich J.
      • Falk W.
      Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity.
      • Akazawa Y.
      • Cazanave S.
      • Mott J.L.
      • Elmi N.
      • Bronk S.F.
      • Kohno S.
      • Charlton M.R.
      • Gores G.J.
      Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis.
      • Granados N.
      • Amengual J.
      • Ribot J.
      • Palou A.
      • Bonet M.L.
      Distinct effects of oleic acid and its trans-isomer elaidic acid on the expression of myokines and adipokines in cell models.
      In fact, MUFA have been reported to promote adipocyte hyperplasia rather than the less desirable cellular enlargement in vivo, in association with blunted expression of inflammasome components and activation of metabolic pathways that portend improved insulin sensitivity.
      • Finucane O.M.
      • Lyons C.L.
      • Murphy A.M.
      • Reynolds C.M.
      • Klinger R.
      • Healy N.P.
      • Cooke A.A.
      • Coll R.C.
      • McAllan L.
      • Nilaweera K.N.
      • O'Reilly M.E.
      • Tierney A.C.
      • Morine M.J.
      • Alcala-Diaz J.F.
      • Lopez-Miranda J.
      • O'Connor D.P.
      • O'Neill L.A.
      • McGillicuddy F.C.
      • Roche H.M.
      Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1beta secretion and insulin resistance despite obesity.
      Interestingly, despite the apparently benign nature of dietary MUFA toward hepatocytes and adipocytes in vitro, some studies indicate that MUFA-enriched diets (see Table 1 for ingredients) induce more hepatic steatosis than isocaloric SFA-enriched diets.
      • Duwaerts C.C.
      • Amin A.M.
      • Siao K.
      • Her C.
      • Fitch M.
      • Beysen C.
      • Turner S.M.
      • Goodsell A.
      • Baron J.L.
      • Grenert J.P.
      • Cho S.J.
      • Maher J.J.
      Specific macronutrients exert unique influences on the adipose-liver axis to promote hepatic steatosis in mice.
      • Hoefel A.L.
      • Hansen F.
      • Rosa P.D.
      • Assis A.M.
      • Silveira S.L.
      • Denardin C.C.
      • Pettenuzzo L.
      • Augusti P.R.
      • Somacal S.
      • Emanuelli T.
      • Perry M.L.
      • Wannmacher C.M.
      The effects of hypercaloric diets on glucose homeostasis in the rat: influence of saturated and monounsaturated dietary lipids.
      • Sampath H.
      • Miyazaki M.
      • Dobrzyn A.
      • Ntambi J.M.
      Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat.
      Pertinent to this point, studies from our laboratory showed that mice fed diets containing 40% kcal MUFA in the form of high-oleate sunflower oil for 6 months developed substantial hepatic steatosis coincident with pronounced adipose tissue injury and inflammation.
      • Duwaerts C.C.
      • Amin A.M.
      • Siao K.
      • Her C.
      • Fitch M.
      • Beysen C.
      • Turner S.M.
      • Goodsell A.
      • Baron J.L.
      • Grenert J.P.
      • Cho S.J.
      • Maher J.J.
      Specific macronutrients exert unique influences on the adipose-liver axis to promote hepatic steatosis in mice.
      In 1 human study, feeding a high concentration of MUFA (44% kcal) for 12 weeks also induced monocyte chemoattractant protein-1 expression in adipose tissue.
      • Meneses M.E.
      • Camargo A.
      • Perez-Martinez P.
      • Delgado-Lista J.
      • Cruz-Teno C.
      • Jimenez-Gomez Y.
      • Paniagua J.A.
      • Gutierrez-Mariscal F.M.
      • Tinahones F.J.
      • Vidal-Puig A.
      • Roche H.M.
      • Perez-Jimenez F.
      • Malagon M.M.
      • Lopez-Miranda J.
      Postprandial inflammatory response in adipose tissue of patients with metabolic syndrome after the intake of different dietary models.
      This raises questions as to whether MUFA are truly nontoxic in vivo, particularly when used in high concentrations in the diet. In humans with NAFLD, the effects of MUFA-enriched “Mediterranean” diets have been explored in a small number of carefully controlled clinical trials. In 2 studies, subjects were fed a MUFA-enriched diet (40% total kcal fat) or a lower-fat nonenriched diet (30% total kcal fat) for 6–8 weeks.
      • Bozzetto L.
      • Prinster A.
      • Annuzzi G.
      • Costagliola L.
      • Mangione A.
      • Vitelli A.
      • Mazzarella R.
      • Longobardo M.
      • Mancini M.
      • Vigorito C.
      • Riccardi G.
      • Rivellese A.A.
      Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients.
      • Ryan M.C.
      • Itsiopoulos C.
      • Thodis T.
      • Ward G.
      • Trost N.
      • Hofferberth S.
      • O'Dea K.
      • Desmond P.V.
      • Johnson N.A.
      • Wilson A.M.
      The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.
      In both cases the MUFA-enriched diet substantially reduced hepatic steatosis and improved insulin sensitivity more than the comparison diet, but other measures were equivalent. A third study was recently published that tested similar diets for 12 weeks. Unlike the earlier studies, this one showed improvement in hepatic steatosis with both the MUFA-enriched diet and the low-fat diet, with no significant difference between the 2.
      • Properzi C.
      • O'Sullivan T.A.
      • Sherriff J.L.
      • Ching H.L.
      • Jeffrey G.P.
      • Buckley R.F.
      • Tibballs J.
      • MacQuillan G.C.
      • Garas G.
      • Adams L.A.
      Ad libitum Mediterranean and low-fat diets both significantly reduce hepatic steatosis: a randomized controlled trial.
      Experts are now calling for further investigation of MUFA-enriched diets in patients with NAFLD that include extended treatment intervals and robust liver and adipose tissue outcome measures.
      • Targher G.
      • Byrne C.D.
      Ad libitum Mediterranean or low fat diets as treatments for non-alcoholic fatty liver disease?.
      One important caveat is that Mediterranean diets, although enriched in MUFA, may also contain higher levels of PUFA than comparison diets. This can make it difficult to assign any benefit of a Mediterranean diet specifically to MUFA. Until further evidence is collected, the specific benefit of MUFA for metabolic health remains uncertain.
      Table 1Types of Monounsaturated Fatty Acid Used in Individual Animal and Human Studies
      ReferenceAuthorSpeciesDietary monounsaturated fatty acidNotes
      • Duwaerts C.C.
      • Amin A.M.
      • Siao K.
      • Her C.
      • Fitch M.
      • Beysen C.
      • Turner S.M.
      • Goodsell A.
      • Baron J.L.
      • Grenert J.P.
      • Cho S.J.
      • Maher J.J.
      Specific macronutrients exert unique influences on the adipose-liver axis to promote hepatic steatosis in mice.
      Duwaerts et alAnimalHigh-oleate sunflower oil
      • Hoefel A.L.
      • Hansen F.
      • Rosa P.D.
      • Assis A.M.
      • Silveira S.L.
      • Denardin C.C.
      • Pettenuzzo L.
      • Augusti P.R.
      • Somacal S.
      • Emanuelli T.
      • Perry M.L.
      • Wannmacher C.M.
      The effects of hypercaloric diets on glucose homeostasis in the rat: influence of saturated and monounsaturated dietary lipids.
      Hoefel et alAnimalOlive oil
      • Sampath H.
      • Miyazaki M.
      • Dobrzyn A.
      • Ntambi J.M.
      Stearoyl-CoA desaturase-1 mediates the pro-lipogenic effects of dietary saturated fat.
      Sampath et alAnimalTriolein
      • Meneses M.E.
      • Camargo A.
      • Perez-Martinez P.
      • Delgado-Lista J.
      • Cruz-Teno C.
      • Jimenez-Gomez Y.
      • Paniagua J.A.
      • Gutierrez-Mariscal F.M.
      • Tinahones F.J.
      • Vidal-Puig A.
      • Roche H.M.
      • Perez-Jimenez F.
      • Malagon M.M.
      • Lopez-Miranda J.
      Postprandial inflammatory response in adipose tissue of patients with metabolic syndrome after the intake of different dietary models.
      Meneses et alHumanOlive oil–enriched mayonnaise, nutsLIPGENE Study
      • Bozzetto L.
      • Prinster A.
      • Annuzzi G.
      • Costagliola L.
      • Mangione A.
      • Vitelli A.
      • Mazzarella R.
      • Longobardo M.
      • Mancini M.
      • Vigorito C.
      • Riccardi G.
      • Rivellese A.A.
      Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients.
      Bozzetto et alHumanOlive oil
      • Ryan M.C.
      • Itsiopoulos C.
      • Thodis T.
      • Ward G.
      • Trost N.
      • Hofferberth S.
      • O'Dea K.
      • Desmond P.V.
      • Johnson N.A.
      • Wilson A.M.
      The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.
      Ryan et alHumanOlive oil, nuts, olives, fishMediterranean
      • Properzi C.
      • O'Sullivan T.A.
      • Sherriff J.L.
      • Ching H.L.
      • Jeffrey G.P.
      • Buckley R.F.
      • Tibballs J.
      • MacQuillan G.C.
      • Garas G.
      • Adams L.A.
      Ad libitum Mediterranean and low-fat diets both significantly reduce hepatic steatosis: a randomized controlled trial.
      Properzi et alHumanOlive oil, nuts, fishMediterranean

      Polyunsaturated Fatty Acid

      PUFA are generally characterized as beneficial to metabolic health, particularly in relation to SFA. PUFA, however, are divided into 2 major subspecies (ω-3 and ω-6 PUFA) that can have different effects on tissue biology. For example, ω-3 PUFA can suppress inflammation through the generation of specialized proresolving mediators,
      • Barden A.E.
      • Mas E.
      • Mori T.A.
      n-3 Fatty acid supplementation and proresolving mediators of inflammation.
      whereas ω-6 PUFA can promote inflammation by conversion to arachidonic acid and other inflammatory eicosanoids
      • Innes J.K.
      • Calder P.C.
      Omega-6 fatty acids and inflammation.
      (reviewed in
      • Scorletti E.
      • Byrne C.D.
      Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease.
      ). The average Western diet contains far less ω-3 PUFA than ω-6 PUFA.
      • Scorletti E.
      • Byrne C.D.
      Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.
      • Scorletti E.
      • Byrne C.D.
      Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease.
      • Jump D.B.
      • Lytle K.A.
      • Depner C.M.
      • Tripathy S.
      Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease.
      Consequently, efforts are underway to encourage incorporation of more ω-3 PUFA into the diet or the use of ω-3 PUFA supplements, or both.
      • Jump D.B.
      • Lytle K.A.
      • Depner C.M.
      • Tripathy S.
      Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease.
      Among the beneficial effects of PUFA, regardless of subspecies, are their ability to suppress lipogenesis and stimulate fatty acid oxidation by downregulating sterol regulatory element-binding protein-1, carbohydrate-responsive element-binding protein, and farnesoid X receptor and activating peroxisome proliferator-activated receptor-α.
      • Dentin R.
      • Benhamed F.
      • Pegorier J.P.
      • Foufelle F.
      • Viollet B.
      • Vaulont S.
      • Girard J.
      • Postic C.
      Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation.
      • Kliewer S.A.
      • Sundseth S.S.
      • Jones S.A.
      • Brown P.J.
      • Wisely G.B.
      • Koble C.S.
      • Devchand P.
      • Wahli W.
      • Willson T.M.
      • Lenhard J.M.
      • Lehmann J.M.
      Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma.
      • Xu J.
      • Nakamura M.T.
      • Cho H.P.
      • Clarke S.D.
      Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats.
      • Zhao A.
      • Yu J.
      • Lew J.L.
      • Huang L.
      • Wright S.D.
      • Cui J.
      Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets.
      In addition, ω-3 and ω-6 PUFA have both been shown to suppress nuclear factor-κB, inflammasome activation, and promote autophagy in hepatocytes.
      • Shen L.
      • Yang Y.
      • Ou T.
      • Key C.C.
      • Tong S.H.
      • Sequeira R.C.
      • Nelson J.M.
      • Nie Y.
      • Wang Z.
      • Boudyguina E.
      • Shewale S.V.
      • Zhu X.
      Dietary PUFAs attenuate NLRP3 inflammasome activation via enhancing macrophage autophagy.
      • Sui Y.H.
      • Luo W.J.
      • Xu Q.Y.
      • Hua J.
      Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation.
      Similarly, ω-3 and ω-6 PUFA are both capable of suppressing adipocyte hypertrophy and preventing inflammation and fibrosis in adipose tissue,
      • Bradley R.L.
      • Fisher F.F.
      • Maratos-Flier E.
      Dietary fatty acids differentially regulate production of TNF-alpha and IL-10 by murine 3T3-L1 adipocytes.
      • Yeop Han C.
      • Kargi A.Y.
      • Omer M.
      • Chan C.K.
      • Wabitsch M.
      • O'Brien K.D.
      • Wight T.N.
      • Chait A.
      Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation.
      • Bargut T.C.
      • Mandarim-de-Lacerda C.A.
      • Aguila M.B.
      A high-fish-oil diet prevents adiposity and modulates white adipose tissue inflammation pathways in mice.
      • Huber J.
      • Loffler M.
      • Bilban M.
      • Reimers M.
      • Kadl A.
      • Todoric J.
      • Zeyda M.
      • Geyeregger R.
      • Schreiner M.
      • Weichhart T.
      • Leitinger N.
      • Waldhausl W.
      • Stulnig T.M.
      Prevention of high-fat diet-induced adipose tissue remodeling in obese diabetic mice by n-3 polyunsaturated fatty acids.
      although there may be some selective benefit of ω-3 over ω-6 PUFA.
      • Huber J.
      • Loffler M.
      • Bilban M.
      • Reimers M.
      • Kadl A.
      • Todoric J.
      • Zeyda M.
      • Geyeregger R.
      • Schreiner M.
      • Weichhart T.
      • Leitinger N.
      • Waldhausl W.
      • Stulnig T.M.
      Prevention of high-fat diet-induced adipose tissue remodeling in obese diabetic mice by n-3 polyunsaturated fatty acids.
      In a study of mice in vivo, ω-3 PUFA supplementation could prevent and reverse high-fat diet-induced hepatic steatosis.
      • Kalupahana N.S.
      • Claycombe K.
      • Newman S.J.
      • Stewart T.
      • Siriwardhana N.
      • Matthan N.
      • Lichtenstein A.H.
      • Moustaid-Moussa N.
      Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation.
      Although in another study ω-6 PUFA did not achieve the same reduction in liver fat,
      • Gentile C.L.
      • Weir T.L.
      • Cox-York K.A.
      • Wei Y.
      • Wang D.
      • Reese L.
      • Moran G.
      • Estrada A.
      • Mulligan C.
      • Pagliassotti M.J.
      • Foster M.T.
      The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD.
      ω-3 and ω-6 PUFA both seem capable of preventing diet-induced insulin resistance and avoiding the diet-induced ER stress and inflammatory changes in the liver that occur with SFA-enriched diets.
      • Gentile C.L.
      • Weir T.L.
      • Cox-York K.A.
      • Wei Y.
      • Wang D.
      • Reese L.
      • Moran G.
      • Estrada A.
      • Mulligan C.
      • Pagliassotti M.J.
      • Foster M.T.
      The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD.
      • Kalupahana N.S.
      • Claycombe K.
      • Newman S.J.
      • Stewart T.
      • Siriwardhana N.
      • Matthan N.
      • Lichtenstein A.H.
      • Moustaid-Moussa N.
      Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation.
      In humans, some trials have compared PUFA-enriched diets (ω-3 or ω-6) with diets with other fats,
      • Meneses M.E.
      • Camargo A.
      • Perez-Martinez P.
      • Delgado-Lista J.
      • Cruz-Teno C.
      • Jimenez-Gomez Y.
      • Paniagua J.A.
      • Gutierrez-Mariscal F.M.
      • Tinahones F.J.
      • Vidal-Puig A.
      • Roche H.M.
      • Perez-Jimenez F.
      • Malagon M.M.
      • Lopez-Miranda J.
      Postprandial inflammatory response in adipose tissue of patients with metabolic syndrome after the intake of different dietary models.
      • Aller R.
      • de Luis D.A.
      • Izaola O.
      • de la Fuente B.
      • Bachiller R.
      Effect of a high monounsaturated vs high polyunsaturated fat hypocaloric diets in nonalcoholic fatty liver disease.
      • Camargo A.
      • Rangel-Zuniga O.A.
      • Alcala-Diaz J.
      • Gomez-Delgado F.
      • Delgado-Lista J.
      • Garcia-Carpintero S.
      • Marin C.
      • Almaden Y.
      • Yubero-Serrano E.M.
      • Lopez-Moreno J.
      • Tinahones F.J.
      • Perez-Martinez P.
      • Roche H.M.
      • Lopez-Miranda J.
      Dietary fat may modulate adipose tissue homeostasis through the processes of autophagy and apoptosis.
      but many more have evaluated the effects of ω-3 PUFA supplements on subjects with fatty liver disease. The results of these trials are elegantly summarized in 2 recent reviews.
      • Scorletti E.
      • Byrne C.D.
      Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.
      • Jump D.B.
      • Lytle K.A.
      • Depner C.M.
      • Tripathy S.
      Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease.
      The consensus opinion is that although some studies report an advantage of ω-3 PUFA supplementation, overall outcomes are variable, and the promise of a therapeutic benefit is dampened by safety concerns related to bleeding and interactions with anticoagulant medications. Until further studies can verify the efficacy of ω-3 PUFA supplements as a therapeutic for NAFLD, experts still recommend incorporating more ω-3 PUFA into the diet in the form of fish and seafood to maintain or improve metabolic health.

      Conclusions

      Overnutrition in any form poses a risk for obesity and fatty liver disease. The specific consequences of overnutrition on adipose tissue and liver, however, depend not only on the amount of energy consumed but also on the type and distribution of macronutrients that make up the diet. Carefully controlled experiments dissecting the impact of individual macronutrients on adipose tissue and liver have enabled their placement into a general rank order on the spectrum of harmful-to-benign. For carbohydrates this is fructose > glucose > starch > fiber, based primarily on their bioavailability to and metabolism within the liver, and for fats the rank is saturated ≥ monounsaturated > polyunsaturated, based on their ability to induce cytotoxicity and their potential to regulate DNL and fatty acid oxidation. The challenge is how to translate the information gained from these experimental studies to real-world situations in which diets are complex and ever-changing. As nutritional research continues, these challenges can be addressed, culminating in the development of sound nutritional guidelines for metabolic health.

      Acknowledgments

      Caroline C. Duwaerts and Jacquelyn J. Maher are responsible for reviewing the literature, drafting of the manuscript, and critical revision of the manuscript.

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