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mTORC2 facilitates liver regeneration through the sphingolipid-induced PPAR-α-fatty acid oxidation

  • Lingling Zhang
    Correspondence
    Correspondence: Lingling Zhang, ;
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China

    Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
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  • Yanqiu Li
    Affiliations
    Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
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  • Ying Wang
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
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  • Yugang Qiu
    Affiliations
    School of Rehabilitation Medicine, Weifang Medical University, Weifang, Shandong, 261053, China
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  • Hanchuan Mou
    Affiliations
    Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
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  • Yuanyao Deng
    Affiliations
    Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
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  • Jiyuan Yao
    Affiliations
    Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China
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  • Zhiqing Xia
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
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  • Wenzhe Zhang
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
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  • Di Zhu
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
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  • Zeyu Qiu
    Affiliations
    School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong S.A.R, China
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  • Zhongjie Lu
    Affiliations
    Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, China
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  • Jirong Wang
    Affiliations
    Zhejiang Provincial Key Lab of Geriatrics & Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, China.
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  • Zhouxin Yang
    Affiliations
    Zhejiang Provincial Key Lab of Geriatrics & Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, China.
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  • GenXiang Mao
    Affiliations
    Zhejiang Provincial Key Lab of Geriatrics & Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, Zhejiang, 310013, China.
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  • Dan Chen
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
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  • Leimin Sun
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China
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  • Leiming Liu
    Correspondence
    Correspondence: Leiming Liu,
    Affiliations
    International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China

    Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
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  • Zhenyu Ju
    Correspondence
    Correspondence: Zhenyu Ju, .
    Affiliations
    Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
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Open AccessPublished:August 02, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.07.011
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      ABSTRACT

      Background & Aims

      During liver regeneration following partial hepatectomy, the function and metabolic pathways governing transient lipid droplet accumulation in hepatocytes remain obscure. Mammalian target of rapamycin 2 (mTORC2) facilitates de novo synthesis of hepatic lipids. Under normal conditions and in tumorigenesis, decreased levels of triglyceride (TG) and fatty acids (FAs) are observed in the mTORC2-deficient liver. However, during liver regeneration, their levels increase in the absence of mTORC2.

      Methods

      Rictor liver-specific knockout (R-LKO) and control mice underwent partial hepatectomy, followed by measurement of TG and FA contents during liver regeneration. FA metabolism was evaluated by analyzing the expression of FA metabolism-related genes and proteins. Intraperitoneal injection of the peroxisome proliferator-activated receptor α (PPAR-α) agonist, p53 inhibitor, and AKT activator was performed to verify the regulatory pathways involved. Lipid mass spectrometry was performed to identify the potential PPAR-α activators.

      Results

      The expression of FA metabolism-related genes and proteins suggested that FAs are mainly transported into hepatocytes during liver regeneration. The PPAR-α pathway is significantly downregulated in the mTORC2-deficient liver, resulting in the accumulation of TGs. The PPAR-α agonist WY-14643 rescued deficient liver regeneration and survival in mTORC2-deficient mice. Furthermore, lipidomic analysis suggested that mTORC2 deficiency substantially reduced glucosylceramide (GluCer) content. GluCer activated PPAR-α. GluCer treatment in vivo restored the regenerative ability and survival rates in the mTORC2-deficient group.

      Conclusions

      Our data suggest that FAs are mainly transported into hepatocytes during liver regeneration, and their metabolism is facilitated by mTORC2 through the GluCer-PPAR-α pathway, thereby establishing a novel role for mTORC2 in lipid metabolism.

      Key words

      List of Abbreviations:

      Acaa1 (acetyl-CoA acyltransferase 1), Acly (ATP-citrate lyase), Acox1 (acyl-CoA oxidase 1), BrdU (5-Bromo-2'-deoxyuridine), CD36 (cluster of differentiation 36), CHOL (cholesterol), Cytb (cytochrome B), Dgat1 (diacylglycerol acyltransferase 1), Elovl5/6 (elongation of very long-chain fatty acids protein 5/6), FABP4 (fatty acid-binding protein 4), Fasn (fatty acid synthase), FA (fatty acid), FoxO1 (forkhead box O 1), GluCer (glucosylceramide), GPL (glycerophospholipids), Hadh (hydroxyacyl-CoA dehydrogenase), HDL-c (high-density lipoprotein cholesterol), Hmgcl (hydroxymethylglutaryl-CoA lyase), Hmgcs2 (hydroxymethylglutaryl-CoA synthase), LDL-c (low-density lipoprotein cholesterol), mTORC2 (mammalian target of rapamycin complex 2), MTTP (microsomal triglyceride transfer protein), PCNA (proliferating cell nuclear antigen), PFT-α (pifithrin-α), PH (partial hepatectomy), PPAR-α (peroxisome proliferator-activated receptor α), R-LKO (liver-specific knockout Rictor), Scl27a2 and Scl27a5 (solute carrier family 27 member 2 and 5), SP (sphingolipids), SPT (serine palmitoyltransferase), SREBP1c (sterol regulatory element-binding transcription factor 1c), VLFA (very long-chain fatty acids), TG (triglyceride)