Advertisement

STARD1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway

  • Laura Conde de la Rosa
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
    Search for articles by this author
  • Carmen Garcia-Ruiz
    Correspondence
    Corresponding authors. Address: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

    Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    Search for articles by this author
  • Carmen Vallejo
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
    Search for articles by this author
  • Anna Baulies
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
    Search for articles by this author
  • Susana Nuñez
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
    Search for articles by this author
  • Maria J. Monte
    Affiliations
    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

    Experimental Hepatology and Drug Targeting (HEVEFARM), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
    Search for articles by this author
  • Jose J.G. Marin
    Affiliations
    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

    Experimental Hepatology and Drug Targeting (HEVEFARM), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
    Search for articles by this author
  • Lucia Baila-Rueda
    Affiliations
    Instituto Investigación Sanitaria Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain

    CIBERCV, Madrid, Spain
    Search for articles by this author
  • Ana Cenarro
    Affiliations
    Instituto Investigación Sanitaria Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain

    CIBERCV, Madrid, Spain
    Search for articles by this author
  • Fernando Civeira
    Affiliations
    Instituto Investigación Sanitaria Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain

    CIBERCV, Madrid, Spain
    Search for articles by this author
  • Josep Fuster
    Affiliations
    HepatoBilioPancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDiM, Hospital Clinic, University of Barcelona, Barcelona, Spain
    Search for articles by this author
  • Juan C. Garcia-Valdecasas
    Affiliations
    HepatoBilioPancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDiM, Hospital Clinic, University of Barcelona, Barcelona, Spain
    Search for articles by this author
  • Joana Ferrer
    Affiliations
    HepatoBilioPancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDiM, Hospital Clinic, University of Barcelona, Barcelona, Spain
    Search for articles by this author
  • Michael Karin
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
    Search for articles by this author
  • Vicent Ribas
    Correspondence
    Corresponding authors. Address: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
    Search for articles by this author
  • Jose C. Fernandez-Checa
    Correspondence
    Corresponding authors. Address: Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain
    Affiliations
    Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain

    Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

    Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    Search for articles by this author
Published:January 27, 2021DOI:https://doi.org/10.1016/j.jhep.2021.01.028

      Highlights

      • Human non-alcoholic fatty liver disease and steatohepatitis-driven HCC tissue specimens exhibit increased STARD1 expression.
      • STARD1 overexpression promotes, whereas STARD1 ablation curtails, NASH-driven HCC.
      • STARD1 stimulates bile acid synthesis through activation of the alternative mitochondrial pathway.
      • Bile acids stimulate pluripotency, stemness and inflammation-related genes in tumour-initiating stem-like cells.

      Background & Aims

      Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored.

      Methods

      STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs).

      Results

      Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation.

      Conclusions

      The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation.

      Lay summary

      Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bianchini F.
        • Kaaks R.
        • Vainio H.
        Overweight, obesity, and cancer risk.
        Lancet Oncol. 2002; 3: 565-574
        • Calle E.E.
        • Rodriguez C.
        • Walker-Thurmond K.
        • Thun M.J.
        Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.
        N Engl J Med. 2003; 348: 1625-1638
        • Forner A.
        • Reig M.
        • Bruix J.
        Hepatocellular carcinoma.
        Lancet. 2018; 391: 1301-1314
        • Bruix J.
        • Reig M.
        • Sherman M.
        Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma.
        Gastroenterology. 2016; 150: 835-853
        • Villanueva A.
        • Hernandez-Gea V.
        • Llovet J.M.
        Medical therapies for hepatocellular carcinoma: a critical view of the evidence.
        Nat Rev Gastroenterol Hepatol. 2013; 10: 34-42
        • Marin J.J.G.
        • Herraez E.
        • Lozano E.
        • Macias R.I.R.
        • Briz O.
        Models for understanding resistance to chemotherapy in liver cancer.
        Cancers (Basel). 2019; 11: 1677
        • Park E.J.
        • Lee J.H.
        • Yu G.Y.
        • He G.
        • Ali S.R.
        • Holzer R.G.
        • et al.
        Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression.
        Cell. 2010; 140: 197-208
        • Nakagawa H.
        • Umemura A.
        • Taniguchi K.
        • Font-Burgada J.
        • Dhar D.
        • Ogata H.
        • et al.
        ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development.
        Cancer Cell. 2014; 26: 331-343
        • Febbraio M.A.
        • Reibe S.
        • Shalapour S.
        • Ooi G.J.
        • Watt M.J.
        • Karin M.
        Preclinical models for studying NASH-driven HCC: how useful are they?.
        Cell Metab. 2019; 29: 18-26
        • Che L.
        • Chi W.
        • Qiao Y.
        • Zhang J.
        • Song X.
        • Liu Y.
        • et al.
        Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans.
        Gut. 2020; 69: 177-186
        • Liang J.Q.
        • Teoh N.
        • Xu L.
        • Pok S.
        • Li X.
        • Chu E.S.H.
        • et al.
        Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling.
        Nat Commun. 2018; 9: 4490
        • Bakiri L.
        • Hamacher R.
        • Grana O.
        • Guio-Carrion A.
        • Campos-Olivas R.
        • Martinez L.
        • et al.
        Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation.
        J Exp Med. 2017; 214: 1387-1409
        • Liu D.
        • Wong C.C.
        • Fu L.
        • Chen H.
        • Zhao L.
        • Li C.
        • et al.
        Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target.
        Sci Transl Med. 2018; 10eaap9840
        • Sun L.
        • Beggs K.
        • Borude P.
        • Edwards G.
        • Bhushan B.
        • Walesky C.
        • et al.
        Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling.
        Am J Physiol Gastrointest Liver Physiol. 2016; 311: G91-G104
        • Gadaleta R.M.
        • van Mil S.W.
        • Oldenburg B.
        • Siersema P.D.
        • Klomp L.W.
        • van Erpecum K.J.
        Bile acids and their nuclear receptor FXR: relevance for hepatobiliary and gastrointestinal disease.
        Biochim Biophys Acta. 2010; 1801: 683-692
        • Puri P.
        • Daita K.
        • Joyce A.
        • Mirshahi F.
        • Santhekadur P.K.
        • Cazanave S.
        • et al.
        The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids.
        Hepatology. 2018; 67: 534-548
        • Kim I.
        • Morimura K.
        • Shah Y.
        • Yang Q.
        • Ward J.M.
        • Gonzalez F.J.
        Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice.
        Carcinogenesis. 2007; 28: 940-946
        • Knisely A.S.
        • Strautnieks S.S.
        • Meier Y.
        • Stieger B.
        • Byrne J.A.
        • Portmann B.C.
        • et al.
        Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
        Hepatology. 2006; 44: 478-486
        • Yang F.
        • Huang X.
        • Yi T.
        • Yen Y.
        • Moore D.D.
        • Huang W.
        Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor.
        Cancer Res. 2007; 67: 863-867
        • Mari M.
        • Caballero F.
        • Colell A.
        • Morales A.
        • Caballeria J.
        • Fernandez A.
        • et al.
        Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis.
        Cell Metab. 2006; 4: 185-198
        • Solsona-Vilarrasa E.
        • Fucho R.
        • Torres S.
        • Nunez S.
        • Nuno-Lambarri N.
        • Enrich C.
        • et al.
        Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes.
        Redox Biol. 2019; 24: 101214
        • Montero J.
        • Morales A.
        • Llacuna L.
        • Lluis J.M.
        • Terrones O.
        • Basanez G.
        • et al.
        Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma.
        Cancer Res. 2008; 68: 5246-5256
        • Lucken-Ardjomande S.
        • Montessuit S.
        • Martinou J.C.
        Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes.
        Cell Death Differ. 2008; 15: 484-493
        • Christenson E.
        • Merlin S.
        • Saito M.
        • Schlesinger P.
        Cholesterol effects on BAX pore activation.
        J Mol Biol. 2008; 381: 1168-1183
        • Smith B.
        • Land H.
        Anticancer activity of the cholesterol exporter ABCA1 gene.
        Cell Rep. 2012; 2: 580-590
        • Ribas V.
        • Garcia-Ruiz C.
        • Fernandez-Checa J.C.
        Mitochondria, cholesterol and cancer cell metabolism.
        Clin Transl Med. 2016; 5: 22
        • Alpy F.
        • Tomasetto C.
        START ships lipids across interorganelle space.
        Biochimie. 2014; 96: 85-95
        • Clark B.J.
        The mammalian START domain protein family in lipid transport in health and disease.
        J Endocrinol. 2012; 212: 257-275
        • Elustondo P.
        • Martin L.A.
        • Karten B.
        Mitochondrial cholesterol import.
        Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862: 90-101
        • Pandak W.M.
        • Kakiyama G.
        The acidic pathway of bile acid synthesis: not just an alternative pathway.
        Liver Res. 2019; 3: 88-98
        • Kakiyama G.
        • Marques D.
        • Takei H.
        • Nittono H.
        • Erickson S.
        • Fuchs M.
        • et al.
        Mitochondrial oxysterol biosynthetic pathway gives evidence for CYP7B1 as controller of regulatory oxysterols.
        J Steroid Biochem Mol Biol. 2019; 189: 36-47
        • Vaz F.M.
        • Ferdinandusse S.
        Bile acid analysis in human disorders of bile acid biosynthesis.
        Mol Aspects Med. 2017; 56: 10-24
        • Caballero F.
        • Fernandez A.
        • De Lacy A.M.
        • Fernandez-Checa J.C.
        • Caballeria J.
        • Garcia-Ruiz C.
        Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH.
        J Hepatol. 2009; 50: 789-796
        • Min H.K.
        • Kapoor A.
        • Fuchs M.
        • Mirshahi F.
        • Zhou H.
        • Maher J.
        • et al.
        Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.
        Cell Metab. 2012; 15: 665-674
        • Mazzaferro V.
        • Regalia E.
        • Doci R.
        • Andreola S.
        • Pulvirenti A.
        • Bozzetti F.
        • et al.
        Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
        N Engl J Med. 1996; 334: 693-699
        • Torres S.
        • Baulies A.
        • Insausti-Urkia N.
        • Alarcon-Vila C.
        • Fucho R.
        • Solsona-Vilarrasa E.
        • et al.
        Endoplasmic reticulum stress-induced upregulation of STARD1 promotes acetaminophen-induced acute liver failure.
        Gastroenterology. 2019; 157: 552-568
        • Weglarz T.C.
        • Degen J.L.
        • Sandgren E.P.
        Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes.
        Am J Pathol. 2000; 157: 1963-1974
        • Baulies A.
        • Montero J.
        • Matias N.
        • Insausti N.
        • Terrones O.
        • Basanez G.
        • et al.
        The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading.
        Redox Biol. 2018; 14: 164-177
        • Chen C.L.
        • Tsukamoto H.
        • Liu J.C.
        • Kashiwabara C.
        • Feldman D.
        • Sher L.
        • et al.
        Reciprocal regulation by TLR4 and TGF-beta in tumor-initiating stem-like cells.
        J Clin Invest. 2013; 123: 2832-2849
        • Arenas F.
        • Castro F.
        • Nunez S.
        • Gay G.
        • Garcia-Ruiz C.
        • Fernandez-Checa J.C.
        STARD1 and NPC1 expression as pathological markers associated with astrogliosis in post-mortem brains from patients with Alzheimer's disease and Down syndrome.
        Aging. 2020; 12: 571-592
        • Kim J.Y.
        • Garcia-Carbonell R.
        • Yamachika S.
        • Zhao P.
        • Dhar D.
        • Loomba R.
        • et al.
        ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P.
        Cell. 2018; 175: 133-145
        • Yang Z.
        • Qin W.
        • Chen Y.
        • Yuan B.
        • Song X.
        • Wang B.
        • et al.
        Cholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts.
        Cancer Lett. 2018; 429: 66-77
        • Zhao Z.
        • Zhong L.
        • He K.
        • Qiu C.
        • Li Z.
        • Zhao L.
        • et al.
        Cholesterol attenuated the progression of DEN-induced hepatocellular carcinoma via inhibiting SCAP mediated fatty acid de novo synthesis.
        Biochem Biophys Res Commun. 2019; 509: 855-861
        • Lee Y.L.
        • Li W.C.
        • Tsai T.H.
        • Chiang H.Y.
        • Ting C.T.
        Body mass index and cholesterol level predict surgical outcome in patients with hepatocellular carcinoma in Taiwan - a cohort study.
        Oncotarget. 2016; 7: 22948-22959
        • Carr B.I.
        • Giannelli G.
        • Guerra V.
        • Giannini E.G.
        • Farinati F.
        • Rapaccini G.L.
        • et al.
        Plasma cholesterol and lipoprotein levels in relation to tumor aggressiveness and survival in HCC patients.
        Int J Biol Markers. 2018; 33: 423-431
        • Qin W.H.
        • Yang Z.S.
        • Li M.
        • Chen Y.
        • Zhao X.F.
        • Qin Y.Y.
        • et al.
        High serum levels of cholesterol increase anti-tumor functions of nature killer cells and reduce growth of liver tumors in mice.
        Gastroenterology. 2020; 158: 1713-1727
        • Jang J.E.
        • Park H.S.
        • Yoo H.J.
        • Baek I.J.
        • Yoon J.E.
        • Ko M.S.
        • et al.
        Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.
        Hepatology. 2017; 66: 416-431
        • Farrell G.
        • Schattenberg J.M.
        • Leclercq I.
        • Yeh M.M.
        • Goldin R.
        • Teoh N.
        • et al.
        Mouse models of nonalcoholic steatohepatitis: toward optimization of their relevance to human nonalcoholic steatohepatitis.
        Hepatology. 2019; 69: 2241-2257
        • Loomba R.
        • Sirlin C.B.
        • Ang B.
        • Bettencourt R.
        • Jain R.
        • Salotti J.
        • et al.
        Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).
        Hepatology. 2015; 61: 1239-1250
        • Miura K.
        • Ohnishi H.
        • Morimoto N.
        • Minami S.
        • Ishioka M.
        • Watanabe S.
        • et al.
        Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet.
        Cancer Sci. 2019; 110: 771-783
        • Lobo N.A.
        • Shimono Y.
        • Qian D.
        • Clarke M.F.
        The biology of cancer stem cells.
        Annu Rev Cell Dev Biol. 2007; 23: 675-699
        • Rountree C.B.
        • Ding W.
        • He L.
        • Stiles B.
        Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensin homolog deleted on chromosome 10-deleted mice.
        Stem Cells. 2009; 27: 290-299
        • Ding W.
        • Mouzaki M.
        • You H.
        • Laird J.C.
        • Mato J.
        • Lu S.C.
        • et al.
        CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-induced apoptosis.
        Hepatology. 2009; 49: 1277-1286
        • Zabulica M.
        • Srinivasan R.C.
        • Vosough M.
        • Hammarstedt C.
        • Wu T.
        • Gramignoli R.
        • et al.
        Guide to the assessment of mature liver gene expression in stem cell-derived hepatocytes.
        Stem Cells Dev. 2019; 28: 907-919
        • Pandak W.M.
        • Ren S.
        • Marques D.
        • Hall E.
        • Redford K.
        • Mallonee D.
        • et al.
        Transport of cholesterol into mitochondria is rate-limiting for bile acid synthesis via the alternative pathway in primary rat hepatocytes.
        J Biol Chem. 2002; 277: 48158-48164
        • Ren S.
        • Hylemon P.B.
        • Marques D.
        • Gurley E.
        • Bodhan P.
        • Hall E.
        • et al.
        Overexpression of cholesterol transporter StAR increases in vivo rates of bile acid synthesis in the rat and mouse.
        Hepatology. 2004; 40: 910-917
        • Henkel A.S.
        • LeCuyer B.
        • Olivares S.
        • Green R.M.
        Endoplasmic reticulum stress regulates hepatic bile acid metabolism in mice.
        Cell Mol Gastroenterol Hepatol. 2017; 3: 261-271
        • Sayin S.I.
        • Wahlstrom A.
        • Felin J.
        • Jantti S.
        • Marschall H.U.
        • Bamberg K.
        • et al.
        Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.
        Cell Metab. 2013; 17: 225-235
        • Worthmann A.
        • John C.
        • Ruhlemann M.C.
        • Baguhl M.
        • Heinsen F.A.
        • Schaltenberg N.
        • et al.
        Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis.
        Nat Med. 2017; 23: 839-849
        • Fan L.
        • Joseph J.F.
        • Durairaj P.
        • Parr M.K.
        • Bureik M.
        Conversion of chenodeoxycholic acid to cholic acid by human CYP8B1.
        Biol Chem. 2019; 400: 625-628