Objective:Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroidhormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes afundamental step in bile acid synthesis.Methods:Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels weremeasured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver celllines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clin-ical biochemistry, and enzyme immunoassays.Results:In human liver biopsies,AKR1D1expression decreased with advancing steatosis,fibrosis and inflamma-tion.Expression was decreasedin patients with type 2 diabetes. In human liver cell lines,AKR1D1knockdown de-creased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption ofkey metabolic pathways, including insulin action and fatty acid metabolism.AKR1D1knockdown increased he-patocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increasedde novolipo-genesis and decreasedβ-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bileacid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the ob-served metabolic phenotype is driven through bile acid rather than steroid hormone availability.Conclusions:Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines,driving steatosis and inflammation. Taken together, the observation thatAKR1D1mRNA is down-regulated withadvancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.
Nikolaou, NikolaosGathercole, Laura L.Marchand, LeaAlthari, SaraDempster, Niall J.Green, Charlotte J.van de Bunt, MartijnMcNeil, CatrionaArvaniti, AnastasiaHughes, Beverly A.Sgromo, BrunoGillies, Richard S.Marschall, Hanns-UlrichPenning, Trevor M.Ryan, JohnArlt, WiebkeHodson, LeanneTomlinson, Jeremy W.
Department of Biological and Medical Sciences
Year of publication: 2019Date of RADAR deposit: 2019-07-31