Lipogenic pathway in NAFLD and NAFLD-related HCC: Friend or Foe?

At present, several drugs targeting enzymes involved in hepatic de novo lipogenesis such as acetyl-CoA carboxylase, fatty acid synthase, and steroyl-CoA desaturase 1 are under development. These enzymes are all regulated by sterol regulatory element-binding protein (SREBP), a master regulator of lipogenesis, and therefore SREBP inhibition could be more effective therapeutic strategy against NAFLD. In this study, we assessed the impact of SREBP inhibition on NASH and hepatocellular carcinoma development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis, despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP-SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 downregulation, which led to endoplasmic reticulum stress and hepatocyte injury. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy, which will have important clinical implications in NASH treatment.