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
Graphical Abstract
Keywords
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Article info
Publication history
Published online: January 27, 2021
Accepted:
January 13,
2021
Received in revised form:
January 10,
2021
Received:
June 19,
2020
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
