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Dysregulation of Lipid and Glucose Homeostasis in Hepatocyte-Specific SLC25A34 Knockout Mice

  • Nairita Roy
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Frances Alencastro
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Bayley A. Roseman
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Sierra R. Wilson
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Evan R. Delgado
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Meredith C. May
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Bharat Bhushan
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Fiona M. Bello
    Affiliations
    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Michael J. Jurczak
    Affiliations
    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Sruti Shiva
    Affiliations
    Departments of Pharmacology and Chemical Biology, Vascular Medicine Institute, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Joseph Locker
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Sebastien Gingras
    Affiliations
    Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Andrew W. Duncan
    Correspondence
    Address correspondence to Andrew W. Duncan, Ph.D., Department of Pathology, McGowan Institute, PLRC, University of Pittsburgh, 450 Technology Dr., Ste 300, Pittsburgh, PA 15219.
    Affiliations
    Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Bioengineering, School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
      Nonalcoholic fatty liver disease (NAFLD) is an epidemic affecting 30% of the US population. NAFLD is characterized by insulin resistance and by defective lipid metabolism and mitochondrial dysfunction in the liver. SLC25A34 is a major repressive target of miRNA-122, a miRNA that has a central role in NAFLD and liver cancer. However, little is known about the function of SLC25A34. To investigate SLC25A34 in vitro, mitochondrial respiration and bioenergetics were examined using hepatocytes depleted of Slc25a34 or overexpressing Slc25a34. To test the function of SLC25A34 in vivo, a hepatocyte-specific knockout mouse was generated, and loss of SLC25A34 was assessed in mice maintained on a chow diet and a fast-food diet (FFD), a model for NAFLD. Hepatocytes depleted of Slc25a34 displayed increased mitochondrial biogenesis, lipid synthesis, and ADP/ATP ratio; Slc25a34 overexpression had the opposite effect. In the knockout model on chow diet, SLC25A34 loss modestly affected liver function (altered glucose metabolism was the most pronounced defect). RNA-sequencing revealed changes in metabolic processes, especially fatty acid metabolism. After 2 months of FFD, knockouts had a more severe phenotype, with increased lipid content and impaired glucose tolerance, which was attenuated after longer FFD feeding (6 months). This work thus presents a novel model for studying SLC25A34 in vivo in which SLC25A34 plays a role in mitochondrial respiration and bioenergetics during NAFLD.
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      References

        • Palmieri F.
        • Monné M.
        Discoveries, metabolic roles and diseases of mitochondrial carriers: a review.
        Biochim Biophys Acta. 2016; 1863: 2362-2378
        • Ruprecht J.J.
        • Kunji E.R.S.
        The SLC25 mitochondrial carrier family: structure and mechanism.
        Trends Biochem Sci. 2020; 45: 244-258
        • Palmieri L.
        • Vozza A.
        • Agrimi G.
        • De Marco V.
        • Runswick M.J.
        • Palmieri F.
        • Walker J.E.
        Identification of the yeast mitochondrial transporter for oxaloacetate and sulfate.
        J Biol Chem. 1999; 274: 22184-22190
        • Marobbio C.M.
        • Giannuzzi G.
        • Paradies E.
        • Pierri C.L.
        • Palmieri F.
        alpha-Isopropylmalate, a leucine biosynthesis intermediate in yeast, is transported by the mitochondrial oxalacetate carrier.
        J Biol Chem. 2008; 283: 28445-28453
        • Pedroso J.A.
        • Zampieri T.T.
        • Donato Jr., J.
        Reviewing the effects of L-leucine supplementation in the regulation of food intake, energy balance, and glucose homeostasis.
        Nutrients. 2015; 7: 3914-3937
        • Rui L.
        Energy metabolism in the liver.
        Compr Physiol. 2014; 4: 177-197
        • Trefts E.
        • Gannon M.
        • Wasserman D.H.
        The liver.
        Curr Biol. 2017; 27: R1147-R1151
        • Schuppan D.
        • Schattenberg J.M.
        Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches.
        J Gastroenterol Hepatol. 2013; 28: 68-76
        • Ahmed M.
        Non-alcoholic fatty liver disease in 2015.
        World J Hepatol. 2015; 7: 1450-1459
        • Younossi Z.M.
        Non-alcoholic fatty liver disease—a global public health perspective.
        J Hepatol. 2019; 70: 531-544
        • Hsu S.-H.
        • Delgado E.R.
        • Otero P.A.
        • Teng K.-Y.
        • Kutay H.
        • Meehan K.M.
        • Moroney J.B.
        • Monga J.K.
        • Hand N.J.
        • Friedman J.R.
        • Ghoshal K.
        • Duncan A.W.
        MicroRNA-122 regulates polyploidization in the murine liver.
        Hepatology. 2016; 64: 599-615
        • Hsu S.-H.
        • Wang B.
        • Kota J.
        • Yu J.
        • Costinean S.
        • Kutay H.
        • Yu L.
        • Bai S.
        • La Perle K.
        • Chivukula R.R.
        • Mao H.
        • Wei M.
        • Clark K.R.
        • Mendell J.R.
        • Caligiuri M.A.
        • Jacob S.T.
        • Mendell J.T.
        • Ghoshal K.
        Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.
        J Clin Invest. 2012; 122: 2871-2883
        • Hsu S.-H.
        • Wang B.
        • Kutay H.
        • Bid H.
        • Shreve J.
        • Zhang X.
        • Costinean S.
        • Bratasz A.
        • Houghton P.
        • Ghoshal K.
        Hepatic loss of miR-122 predisposes mice to hepatobiliary cyst and hepatocellular carcinoma upon diethylnitrosamine exposure.
        Am J Pathol. 2013; 183: 1719-1730
        • Kita Y.
        • Takamura T.
        • Misu H.
        • Ota T.
        • Kurita S.
        • Takeshita Y.
        • Uno M.
        • Matsuzawa-Nagata N.
        • Kato K.-I.
        • Ando H.
        • Fujimura A.
        • Hayashi K.
        • Kimura T.
        • Ni Y.
        • Otoda T.
        • Miyamoto K.-I.
        • Zen Y.
        • Nakanuma Y.
        • Kaneko S.
        Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis.
        PLoS One. 2012; 7: e43056
        • Ichimura A.
        • Hirasawa A.
        • Poulain-Godefroy O.
        • Bonnefond A.
        • Hara T.
        • Yengo L.
        • et al.
        Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.
        Nature. 2012; 483: 350-354
        • Pachikian B.D.
        • Essaghir A.
        • Demoulin J.-B.
        • Neyrinck A.M.
        • Catry E.
        • De Backer F.C.
        • Dejeans N.
        • Dewulf E.M.
        • Sohet F.M.
        • Portois L.
        • Deldicque L.
        • Molendi-Coste O.
        • Leclercq I.A.
        • Francaux M.
        • Carpentier Y.A.
        • Foufelle F.
        • Muccioli G.G.
        • Cani P.D.
        • Delzenne N.M.
        Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets.
        PLoS One. 2011; 6: e23365
        • Flowers M.T.
        • Groen A.K.
        • Oler A.T.
        • Keller M.P.
        • Choi Y.
        • Schueler K.L.
        • Richards O.C.
        • Lan H.
        • Miyazaki M.
        • Kuipers F.
        • Kendziorski C.M.
        • Ntambi J.M.
        • Attie A.D.
        Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet.
        J Lipid Res. 2006; 47: 2668-2680
        • Keyhani-Nejad F.
        • Irmler M.
        • Isken F.
        • Wirth E.K.
        • Beckers J.
        • Birkenfeld A.L.
        • Pfeiffer A.F.H.
        Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice.
        Diabetologia. 2015; 58: 374-383
        • Anthérieu S.
        • Le Guillou D.
        • Coulouarn C.
        • Begriche K.
        • Trak-Smayra V.
        • Martinais S.
        • Porceddu M.
        • Robin M.-A.
        • Fromenty B.
        Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice.
        Toxicol Appl Pharmacol. 2014; 276: 63-72
        • Ren H.
        • Aleksunes L.M.
        • Wood C.
        • Vallanat B.
        • George M.H.
        • Klaassen C.D.
        • Corton J.C.
        Characterization of peroxisome proliferator-activated receptor alpha–independent effects of PPARalpha activators in the rodent liver: di-(2-ethylhexyl) phthalate also activates the constitutive-activated receptor.
        Toxicol Sci. 2010; 113: 45-59
        • Khetchoumian K.
        • Teletin M.
        • Tisserand J.
        • Mark M.
        • Herquel B.
        • Ignat M.
        • Zucman-Rossi J.
        • Cammas F.
        • Lerouge T.
        • Thibault C.
        • Metzger D.
        • Chambon P.
        • Losson R.
        Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha.
        Nat Genet. 2007; 39: 1500-1506
        • Herrema H.
        • Derks T.G.J.
        • van Dijk T.H.
        • Bloks V.W.
        • Gerding A.
        • Havinga R.
        • Tietge U.J.F.
        • Müller M.
        • Smit G.P.A.
        • Kuipers F.
        • Reijngoud D.-J.
        Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice.
        Hepatology. 2008; 47: 1894-1904
        • Alam M.S.
        • Getz M.
        • Safeukui I.
        • Yi S.
        • Tamez P.
        • Shin J.
        • Velázquez P.
        • Haldar K.
        Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder.
        PLoS One. 2012; 7: e48273
        • Mistry P.K.
        • Liu J.
        • Yang M.
        • Nottoli T.
        • McGrath J.
        • Jain D.
        • Zhang K.
        • Keutzer J.
        • Chuang W.-L.
        • Mehal W.Z.
        • Zhao H.
        • Lin A.
        • Mane S.
        • Liu X.
        • Peng Y.Z.
        • Li J.H.
        • Agrawal M.
        • Zhu L.-L.
        • Blair H.C.
        • Robinson L.J.
        • Iqbal J.
        • Sun L.
        • Zaidi M.
        Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage.
        Proc Natl Acad Sci U S A. 2010; 107: 19473-19478
        • Nakai Y.
        • Hashida H.
        • Kadota K.
        • Minami M.
        • Shimizu K.
        • Matsumoto I.
        • Kato H.
        • Abe K.
        Up-regulation of genes related to the ubiquitin-proteasome system in the brown adipose tissue of 24-h-fasted rats.
        Biosci Biotechnol Biochem. 2008; 72: 139-148
        • Arendt B.M.
        • Comelli E.M.
        • Ma D.W.
        • Lou W.
        • Teterina A.
        • Kim T.
        • Fung S.K.
        • Wong D.K.H.
        • McGilvray I.
        • Fischer S.E.
        • Allard J.P.
        Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids.
        Hepatology. 2015; 61: 1565-1578
        • Lake A.D.
        • Novak P.
        • Fisher C.D.
        • Jackson J.P.
        • Hardwick R.N.
        • Billheimer D.D.
        • Klimecki W.T.
        • Cherrington N.J.
        Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease.
        Drug Metab Dispos. 2011; 39: 1954-1960
        • Quadros R.M.
        • Miura H.
        • Harms D.W.
        • Akatsuka H.
        • Sato T.
        • Aida T.
        • Redder R.
        • Richardson G.P.
        • Inagaki Y.
        • Sakai D.
        • Buckley S.M.
        • Seshacharyulu P.
        • Batra S.K.
        • Behlke M.A.
        • Zeiner S.A.
        • Jacobi A.M.
        • Izu Y.
        • Thoreson W.B.
        • Urness L.D.
        • Mansour S.L.
        • Ohtsuka M.
        • Gurumurthy C.B.
        Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins.
        Genome Biol. 2017; 18: 92
        • Pelletier S.
        • Gingras S.
        • Green D.R.
        Mouse genome engineering via CRISPR-Cas9 for study of immune function.
        Immunity. 2015; 42: 18-27
        • Song A.J.
        • Palmiter R.D.
        Detecting and avoiding problems when using the Cre-lox system.
        Trends Genet. 2018; 34: 333-340
        • Bhushan B.
        • Molina L.
        • Koral K.
        • Stoops J.W.
        • Mars W.M.
        • Banerjee S.
        • Orr A.
        • Paranjpe S.
        • Monga S.P.
        • Locker J.
        • Michalopoulos G.K.
        Yes-associated protein is crucial for constitutive androstane receptor-driven hepatocyte proliferation but not for induction of drug metabolism genes in mice.
        Hepatology. 2021; 73: 2005-2022
        • Bhushan B.
        • Banerjee S.
        • Paranjpe S.
        • Koral K.
        • Mars W.M.
        • Stoops J.W.
        • Orr A.
        • Bowen W.C.
        • Locker J.
        • Michalopoulos G.K.
        Pharmacologic inhibition of epidermal growth factor receptor suppresses nonalcoholic fatty liver disease in a murine fast-food diet model.
        Hepatology. 2019; 70: 1546-1563
        • Overturf K.
        • Al-Dhalimy M.
        • Tanguay R.
        • Brantly M.
        • Ou C.N.
        • Finegold M.
        • Grompe M.
        Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.
        Nat Genet. 1996; 12: 266-273
        • Guo W.
        • Jiang L.
        • Bhasin S.
        • Khan S.M.
        • Swerdlow R.H.
        DNA extraction procedures meaningfully influence qPCR-based mtDNA copy number determination.
        Mitochondrion. 2009; 9: 261-265
        • Park J.
        • Kim J.
        • Mikami T.
        Exercise-induced lactate release mediates mitochondrial biogenesis in the hippocampus of mice via monocarboxylate transporters.
        Front Physiol. 2021; 12: 736905
        • Marquez M.P.
        • Alencastro F.
        • Madrigal A.
        • Jimenez J.L.
        • Blanco G.
        • Gureghian A.
        • Keagy L.
        • Lee C.
        • Liu R.
        • Tan L.
        • Deignan K.
        • Armstrong B.
        • Zhao Y.
        The role of cellular proliferation in adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells.
        Stem Cells Dev. 2017; 26: 1578-1595
        • Silva D.F.
        • Selfridge J.E.
        • Lu J.
        • Lezi E.
        • Roy N.
        • Hutfles L.
        • Burns J.M.
        • Michaelis E.K.
        • Yan S.
        • Cardoso S.M.
        • Swerdlow R.H.
        Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines.
        Hum Mol Genet. 2013; 22: 3931-3946
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • Behling C.
        • Contos M.J.
        • Cummings O.W.
        • Ferrell L.D.
        • Liu Y.-C.
        • Torbenson M.S.
        • Unalp-Arida A.
        • Yeh M.
        • McCullough A.J.
        • Sanyal A.J.
        • Nonalcoholic Steatohepatitis Clinical Research Network
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Edmunds L.R.
        • Huckestein B.R.
        • Kahn M.
        • Zhang D.
        • Chu Y.
        • Zhang Y.
        • Wendell S.G.
        • Shulman G.I.
        • Jurczak M.J.
        Hepatic insulin sensitivity is improved in high-fat diet-fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis.
        Physiol Rep. 2019; 7: e14281
        • Alquier T.
        • Poitout V.
        Considerations and guidelines for mouse metabolic phenotyping in diabetes research.
        Diabetologia. 2018; 61: 526-538
        • Benedé-Ubieto R.
        • Estévez-Vázquez O.
        • Ramadori P.
        • Cubero F.J.
        • Nevzorova Y.A.
        Guidelines and considerations for metabolic tolerance tests in mice.
        Diabetes Metab Syndr Obes. 2020; 13: 439-450
        • Edmunds L.R.
        • Xie B.
        • Mills A.M.
        • Huckestein B.R.
        • Undamatla R.
        • Murali A.
        • Pangburn M.M.
        • Martin J.
        • Sipula I.
        • Kaufman B.A.
        • Scott I.
        • Jurczak M.J.
        Liver-specific Prkn knockout mice are more susceptible to diet-induced hepatic steatosis and insulin resistance.
        Mol Metab. 2020; 41: 101051
        • Li P.A.
        • Hou X.
        • Hao S.
        Mitochondrial biogenesis in neurodegeneration.
        J Neurosci Res. 2017; 95: 2025-2029
        • Ipsen D.H.
        • Lykkesfeldt J.
        • Tveden-Nyborg P.
        Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease.
        Cell Mol Life Sci. 2018; 75: 3313-3327
        • Nakamura M.T.
        • Yudell B.E.
        • Loor J.J.
        Regulation of energy metabolism by long-chain fatty acids.
        Prog Lipid Res. 2014; 53: 124-144
        • Jensen T.L.
        • Kiersgaard M.K.
        • Sørensen D.B.
        • Mikkelsen L.F.
        Fasting of mice: a review.
        Lab Anim. 2013; 47: 225-240
        • Ameer F.
        • Scandiuzzi L.
        • Hasnain S.
        • Kalbacher H.
        • Zaidi N.
        De novo lipogenesis in health and disease.
        Metabolism. 2014; 63: 895-902
        • Sanders F.W.
        • Griffin J.L.
        De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose.
        Biol Rev Camb Philos Soc. 2016; 91: 452-468
        • Friedman S.L.
        • Neuschwander-Tetri B.A.
        • Rinella M.
        • Sanyal A.J.
        Mechanisms of NAFLD development and therapeutic strategies.
        Nat Med. 2018; 24: 908-922
        • Charlton M.
        • Krishnan A.
        • Viker K.
        • Sanderson S.
        • Cazanave S.
        • McConico A.
        • Masuoko H.
        • Gores G.
        Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition.
        Am J Physiol Gastrointest Liver Physiol. 2011; 301: G825-G834
        • Ding R.-B.
        • Bao J.
        • Deng C.-X.
        Emerging roles of SIRT1 in fatty liver diseases.
        Int J Biol Sci. 2017; 13: 852-867
        • Schug T.T.
        • Li X.
        Sirtuin 1 in lipid metabolism and obesity.
        Ann Med. 2011; 43: 198-211
        • Chakrabarti A.
        • Membrez M.
        • Morin-Rivron D.
        • Siddharth J.
        • Chou C.J.
        • Henry H.
        • Bruce S.
        • Metairon S.
        • Raymond F.
        • Betrisey B.
        • Loyer C.
        • Parkinson S.J.
        • Masoodi M.
        Transcriptomics-driven lipidomics (TDL) identifies the microbiome-regulated targets of ileal lipid metabolism.
        NPJ Syst Biol Appl. 2017; 3: 33
        • Fu S.
        • Yang L.
        • Li P.
        • Hofmann O.
        • Dicker L.
        • Hide W.
        • Lin X.
        • Watkins S.M.
        • Ivanov A.R.
        • Hotamisligil G.S.
        Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
        Nature. 2011; 473: 528-531
        • Han B.
        • Sivaramakrishnan P.
        • Lin C.-C.J.
        • Neve I.A.A.
        • He J.
        • Tay L.W.R.
        • Sowa J.N.
        • Sizovs A.
        • Du G.
        • Wang J.
        • Herman C.
        • Wang M.C.
        Microbial genetic composition tunes host longevity.
        Cell. 2017; 169: 1249-1262.e13
        • Jurczak M.J.
        • Lee A.-H.
        • Jornayvaz F.R.
        • Lee H.-Y.
        • Birkenfeld A.L.
        • Guigni B.A.
        • Kahn M.
        • Samuel V.T.
        • Glimcher L.H.
        • Shulman G.I.
        Dissociation of inositol-requiring enzyme (IRE1[alpha])-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice.
        J Biol Chem. 2012; 287: 2558-2567
        • Al Rijjal D.
        • Liu Y.
        • Lai M.
        • Song Y.
        • Danaei Z.
        • Wu A.
        • Mohan H.
        • Wei L.
        • Schopfer F.J.
        • Dai F.F.
        • Wheeler M.B.
        Vascepa protects against high-fat diet-induced glucose intolerance, insulin resistance, and impaired [beta]-cell function.
        iScience. 2021; 24: 102909
        • Minehira K.
        • Young S.G.
        • Villanueva C.J.
        • Yetukuri L.
        • Oresic M.
        • Hellerstein M.K.
        • Farese Jr., R.V.
        • Horton J.D.
        • Preitner F.
        • Thorens B.
        • Tappy L.
        Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice.
        J Lipid Res. 2008; 49: 2038-2044