Introduction Glucocorticoids have been implicated in the pathogenesis of NAFLD, but as most patients with NAFLD have normal circulating cortisol levels it has been suggested that it is hepatic levels which are important. 5α-reductase (5αR) clears cortisol, as well as converting testosterone to the more active androgen dihydrotestosterone. Its role in the pathogenesis of NAFLD has yet to be determined.
Aim To determine the role of 5αR in the pathogenesis of NAFLD.
Method Human liver samples from patients with NAFLD (scored by Kleiner classification) and normal donor tissue were used for immunohistochemical/real-time PCR analysis. Wild type (WT) (n=20) and 5αR1 knockout (KO) mice (n=20) were fed either normal chow or American lifestyle induced obesity syndrome (ALIOS) diet for 6 or 12 months. ALIOS diet is high in trans-fats and high fructose corn syrup. Glucose tolerance, liver and body weights were recorded and liver histology graded (Kleiner). Hepatic triglycerides and mRNA markers of lipid metabolism were quantified. PanCK immunohistochemistry (oval cell response) was quantified by image analysis.
Results 5αR1 expression in human livers was parenchymal and greater in non-alcoholic steatohepatitis (NASH) livers compared to normal liver and was associated with greater lobular inflammation. 5αR1 gene expression was not affected by NASH severity. ALIOS induced steatohepatitis (6 m) and significant fibrosis (F3 at 12 m) in WT and 5αR1 KO mice. Compared with WT mice, 5αR1 KO mice fed the ALIOS diet demonstrated significantly greater liver weight, steatosis score (median 3 vs 1), and hepatic triglyceride accumulation by 6 months (93.1 vs 62.4 nmol/mg p=0.002). mRNA expression of CPT1α, a key enzyme in hepatic fatty acid β oxidation, was reduced in 5αR1−/− mice. There was a trend (p=0.1) towards worse inflammation (Kleiner lobular inflammation/qPCR for hepatic TNFa) at 6 months in 5αR1 KO mice, but no difference in inflammation or fibrosis at 12 months despite the presence of greater hepatic steatosis. The number of panCK-positive cells observed in WT mice fed ALIOS diet increased significantly with longer duration (0 m 0.15%, 6 m 0.44%, 12 m 0.94%, p=0.028) and at 12 months was significantly greater than mice fed normal chow (0.94% vs 0.18% p=0.03). Despite the absence of cirrhosis 5/10 WT mice developed dysplasia/hepatocellular carcinoma after ALIOS for 12 months vs 0/5 5αR1 KO mice. 5aR1 KO mice had lower numbers of panCK-positive cells (0.62% vs 0.94%) compared to its WT.
Conclusion ALIOS diet induces the entire spectrum of NAFLD from simple steatosis to advanced NASH with fibrosis and HCC, with a mounting oval cell response to increasing duration of diet. 5αR1 KO promotes hepatic steatosis in the absence of worsening fibrosis, attenuates the oval cell response and exerts a protective effect on hepatocarcinogenesis thereby demonstrating the role of 5αR in NAFLD pathogenesis.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.