Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage–activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

[1]  K. Koike,et al.  Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis , 2021, JHEP reports : innovation in hepatology.

[2]  K. Koike,et al.  Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat , 2021, Cancers.

[3]  K. Clément,et al.  Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis , 2020, Science Translational Medicine.

[4]  C. Pavlov,et al.  Effectiveness of phosphatidylcholine as adjunctive therapy in improving liver function tests in patients with non-alcoholic fatty liver disease and metabolic comorbidities: real-life observational study from Russia , 2020, BMJ open gastroenterology.

[5]  Tomoya Yamada,et al.  Gas Chromatography–Mass Spectrometry-Based Metabolomic Analysis of Wagyu and Holstein Beef , 2020, Metabolites.

[6]  Y. Hoshida,et al.  Altered serum acylcarnitine profile is associated with the status of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related hepatocellular carcinoma , 2019, Scientific Reports.

[7]  A. Sanyal.  Past, present and future perspectives in nonalcoholic fatty liver disease , 2019, Nature Reviews Gastroenterology & Hepatology.

[8]  P. Tontonoz,et al.  Phospholipid Remodeling in Physiology and Disease. , 2019, Annual review of physiology.

[9]  K. Koike,et al.  Lipid Metabolic Reprogramming in Hepatocellular Carcinoma , 2018, Cancers.

[10]  A. Sanyal,et al.  Pathogenesis of NASH: the Impact of Multiple Pathways , 2018, Current Hepatology Reports.

[11]  M. Karin,et al.  ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P , 2018, Cell.

[12]  E. Paschetta,et al.  Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. , 2018, Gastroenterology.

[13]  Antonio Felix Conde-Martin,et al.  Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. , 2018, Gastroenterology.

[14]  B. Neuschwander‐Tetri,et al.  Mechanisms of NAFLD development and therapeutic strategies , 2018, Nature Medicine.

[15]  Matthew S. Tremblay,et al.  Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages , 2018, Proceedings of the National Academy of Sciences.

[16]  Gianluca Svegliati-Baroni,et al.  Lipotoxicity and the gut-liver axis in NASH pathogenesis. , 2018, Journal of hepatology.

[17]  T. Ishizuka,et al.  Cardiac overexpression of perilipin 2 induces dynamic steatosis: prevention by hormone-sensitive lipase. , 2017, American journal of physiology. Endocrinology and metabolism.

[18]  Jean-François Deleuze,et al.  Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis , 2017, Nature Communications.

[19]  H. Shimano,et al.  SREBP-regulated lipid metabolism: convergent physiology — divergent pathophysiology , 2017, Nature Reviews Endocrinology.

[20]  Ayae Ikawa-Yoshida,et al.  Hepatocellular carcinoma in a mouse model fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet , 2017, International journal of experimental pathology.

[21]  R. Hammer,et al.  Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice , 2017, eLife.

[22]  S. Davies,et al.  Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease , 2017, Hepatology.

[23]  Y. Moon.  The SCAP/SREBP Pathway: A Mediator of Hepatic Steatosis , 2017, Endocrinology and metabolism.

[24]  S. Qiu,et al.  CCL24 contributes to HCC malignancy via RhoB- VEGFA-VEGFR2 angiogenesis pathway and indicates poor prognosis , 2016, Oncotarget.

[25]  M. Karin,et al.  p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer , 2016, FEBS letters.

[26]  Takao Shimizu,et al.  Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  P. Hanawalt,et al.  Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair , 2016, Cell.

[28]  Hayato Nakagawa.  Recent advances in mouse models of obesity- and nonalcoholic steatohepatitis-associated hepatocarcinogenesis. , 2015, World journal of hepatology.

[29]  J. Mesirov,et al.  The Molecular Signatures Database (MSigDB) hallmark gene set collection. , 2015, Cell systems.

[30]  M. Fischer,et al.  A liquid chromatography-tandem mass spectrometry-based method for the simultaneous determination of hydroxy sterols and bile acids. , 2014, Journal of chromatography. A.

[31]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[32]  M. Karin,et al.  ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. , 2014, Cancer cell.

[33]  Á. Valverde,et al.  Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD , 2014, Cell Death and Disease.

[34]  Cheng Huang.  Natural modulators of liver X receptors. , 2014, Journal of integrative medicine.

[35]  M. Karin,et al.  Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis , 2014, Proceedings of the National Academy of Sciences.

[36]  P. Edwards,et al.  LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. , 2013, Cell metabolism.

[37]  J. Harrow,et al.  Systematic evaluation of spliced alignment programs for RNA-seq data , 2013, Nature Methods.

[38]  Kristen Jepsen,et al.  Identification of Liver Cancer Progenitors Whose Malignant Progression Depends on Autocrine IL-6 Signaling , 2013, Cell.

[39]  Robert Gentleman,et al.  Software for Computing and Annotating Genomic Ranges , 2013, PLoS Comput. Biol..

[40]  Masahira Hattori,et al.  Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome , 2013, Nature.

[41]  S. Cherqui,et al.  Upregulation of the Rab27a-Dependent Trafficking and Secretory Mechanisms Improves Lysosomal Transport, Alleviates Endoplasmic Reticulum Stress, and Reduces Lysosome Overload in Cystinosis , 2013, Molecular and Cellular Biology.

[42]  Yu‐Min Lin,et al.  Hepatocyte Growth Factor Increases Vascular Endothelial Growth Factor-A Production in Human Synovial Fibroblasts through c-Met Receptor Pathway , 2012, PloS one.

[43]  W. Shao,et al.  Expanding roles for SREBP in metabolism. , 2012, Cell metabolism.

[44]  Lars Löfgren,et al.  The BUME method: a novel automated chloroform-free 96-well total lipid extraction method for blood plasma[S] , 2012, Journal of Lipid Research.

[45]  D. Russell,et al.  A comprehensive method for extraction and quantitative analysis of sterols and secosteroids from human plasma[S] , 2012, Journal of Lipid Research.

[46]  Mitchell R. McGill,et al.  Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[47]  Timothy F. Osborne,et al.  SREBPs: metabolic integrators in physiology and metabolism , 2012, Trends in Endocrinology & Metabolism.

[48]  C. Hetz.  The unfolded protein response: controlling cell fate decisions under ER stress and beyond , 2012, Nature Reviews Molecular Cell Biology.

[49]  M. Karin,et al.  Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation , 2011, Cell.

[50]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[51]  Tomoko Nishizawa,et al.  Down-regulation of Srebp-1c Is Associated with the Development of Burned-out Nash Running Title: Down-regulation of Srebp-1c with Nafld Progression , 2022 .

[52]  R. Dwek,et al.  Uptake and trafficking of liposomes to the endoplasmic reticulum , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  S. Matsuda,et al.  Decrease in Membrane Phospholipid Unsaturation Induces Unfolded Protein Response* , 2010, The Journal of Biological Chemistry.

[54]  T. Mak,et al.  Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation , 2008, Autophagy.

[55]  Michelle M Wiest,et al.  A lipidomic analysis of nonalcoholic fatty liver disease , 2007, Hepatology.

[56]  D. Eastmond,et al.  Postulated Carbon Tetrachloride Mode of Action: A Review , 2007, Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews.

[57]  F. Urano,et al.  Autophagy Is Activated for Cell Survival after Endoplasmic ReticulumStress , 2006, Molecular and Cellular Biology.

[58]  Jonathan C. Cohen,et al.  Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands* , 2006, Journal of Biological Chemistry.

[59]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[60]  J. Jessurun,et al.  Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. , 2005, The Journal of clinical investigation.

[61]  T. Mak,et al.  Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. , 2004, The Journal of clinical investigation.

[62]  L. Weber,et al.  Hepatotoxicity and Mechanism of Action of Haloalkanes: Carbon Tetrachloride as a Toxicological Model , 2003, Critical reviews in toxicology.

[63]  R. Hammer,et al.  Diminished Hepatic Response to Fasting/Refeeding and Liver X Receptor Agonists in Mice with Selective Deficiency of Sterol Regulatory Element-binding Protein-1c* , 2002, The Journal of Biological Chemistry.

[64]  R. Hammer,et al.  SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. , 2001, Genes & development.

[65]  T. Sasaki,et al.  T cell-specific loss of Pten leads to defects in central and peripheral tolerance. , 2001, Immunity.

[66]  R. Hammer,et al.  Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. , 1997, The Journal of clinical investigation.

[67]  R. Hammer,et al.  Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. , 1996, The Journal of clinical investigation.