Deciphering the role of ferroptosis in non alcoholic fatty liver disease

Non alcoholic fatty liver disease (NAFLD) represents a leading cause of chronic liver damage, which can progress to non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). It is already known that in the pathogenesis of NAFLD, increased hepatic lipid accumulation results in augmented oxidative stress, which increases organ damage. Therefore, inhibition of ferroptosis,a programmed cell death mechanism based on triggering oxidative stress, is a potential therapeutic option for patients with NAFLD.

In this work, we intended to determine whether a liver parenchymal cell (LPC)-specific conditional deletion of acyl-CoA synthetase long-chain family member 4 (Acsl4LPC-KO) can influence the onset and progression of NAFLD. For this purpose, wild-type (wt) and Acsl4LPC-KO animals were fed a choline deficient high fat diet (CD-HFD) for 20 and 40 weeks, illustrating different stages of metabolic liver damage from NAFLD to cirrhosis with HCC progression as well as the development of metabolic syndrome. Subsequently, the mice were subjected to metabolic analyses.

In contrast to the recently published data by Duan et al. (PMID:34510514), we found no significant differences between Acsl4LPC-KO and wt littermates, neither in the development of NAFLD nor in progression of metabolic syndrome. Moreover, there were no differences in metabolic analyses (weight gain, glucose tolerance test, hepatic steatosis) or NAFLD-associated inflammatory response.

According to our analyses, deletion of Acsl4 and concomitant inhibition of ferroptosis appears to have no effect on NAFLD. Through further lipidome analyses, we aim to identify possible differences in the fat metabolism between Acsl4LPC-KO and wt mice that could explain the diverse phenotype.

Publication History

Article published online:
23 January 2024