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

JOURNAL OF HEPATOLOGY

卷:74

Article

de la Rosa, Laura Conde^1,2,3  Garcia-Ruiz, Carmen^1,2,3,4  Vallejo, Carmen^1,2,3  Baulies, Anna^1,2,3  Nunez, Susana^1,2,3  Monte, Maria J.^3,5  Marin, Jose J. G.^3,5  Baila-Rueda, Lucia^6,7  Cenarro, Ana^6,7  Civeira, Fernando^6,7  Fuster, Josep⁸  Garcia-Valdecasas, Juan C.⁸  Ferrer, Joana⁸  Karin, Michael⁹  Ribas, Vicent^1,2,3  Fernandez-Checa, Jose C.^1,2,3,4 

[1] CSIC, Inst Biomed Res Barcelona IIBB, Dept Cell Death & Proliferat, Barcelona, Spain

[2] Hosp Clin I Prov Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Liver Unit, Barcelona, Spain

[3] Carlos III Natl Inst Hlth, Ctr Study Liver & Gastrointestinal Dis CIBERehd, Madrid, Spain

[4] Univ Southern Calif, Keck Sch Med, Ctr ALPD, Los Angeles, CA 90007 USA

[5] Univ Salamanca, Inst Biomed Res Salamanca IBSAL, Expt Hepatol & Drug Targeting HEVEFARM, Salamanca, Spain

[6] Hosp Univ Miguel Servet, Inst Invest Sanitaria Aragon, Zaragoza, Spain

[7] CIBERCV, Madrid, Spain

[8] Univ Barcelona, HepatoBilioPancreat Surg & Liver & Pancreat Trans, Hosp Clin, Dept Surg,ICMDiM, Barcelona, Spain

[9] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA

关键词: Cholesterol;    Mitochondria;    Bile acids;    Hepatocellular carcinoma;    Oxysterols;    STARD1;   

DOI  :  10.1016/j.jhep.2021.01.028

来源: Elsevier

【 摘 要 】

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 (Stard1(Delta Hep)) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, beta-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1(Delta Hep) 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. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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