Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis

Abstract

Enhanced de novo lipogenesis mediated by sterol regulatory element–binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer 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 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

Lipid balance must be just right to prevent development of severe liver damage

“…These results demonstrated that, while liver deletion of SCAP reduced hepatic steatosis, loss of SREBP-dependent lipogenesis sensitized the liver to NASH, which resulted in increased inflammation and HCC carcinogenesis ( Figure 1 ). There was also a positive association in expression of SCAP and SREBPs in patients with NAFLD, providing some correlative evidence that the proposed pathway also has relevancy in human NASH ( 8 ).…”

“…Similar gene-expression signatures were found in isolated hepatocytes from these mice, confirming that the observed ER stress is a cell-autonomous effect due to SCAP deletion. Consistent with ER stress playing a direct role downstream of SCAP deletion, hepatic overexpression of the ER chaperone GRP78 suppressed activation of the UPR marker CHOP and partially rescued liver injury ( 8 ). SREBPs also control elongation and desaturation of fatty acids ( 10 ).…”

“…In this issue of the JCI , Kawamura, Matsushita, et al ( 8 ) report on their combination of the liver-specific PTEN ΔL mouse with a liver-specific SCAP knockout (PTEN/SCAP ΔL ) to examine the effects of lipid reduction on NAFLD development and the progression to NASH and HCC. Compared with PTEN ΔL mice, PTEN/SCAP ΔL mice showed signs of severe liver disease at only 5 weeks of age, including periportal inflammation and necrosis, which were accompanied by elevated serum levels of liver enzymes and secreted proinflammatory cytokines.…”

“…Kawamura, Matsushita, et al ( 8 ) independently tested the effects of SCAP deletion on NASH progression in a second mouse model in which symptoms develop from a choline-deficient, l –amino acid–defined, high-fat diet (CDAHFD) ( 9). In this model, SCAP deletion also resulted in increased liver tumors, indicating that the phenotype was not specific to PTEN deficiency.…”

“…To investigate the mechanism underlying these unexpected results, Kawamura, Matsushita, and colleagues ( 8 ) performed gene-expression and lipidomic analyses on livers from 5-week-old PTEN/SCAP ΔL and PTEN ΔL mice. RNA-Seq comparisons revealed that genes involved in ER stress and the unfolded protein response (UPR) were increased in PTEN/SCAP ΔL mice, and electron microscopy showed morphological defects in ER structure consistent with ER stress.…”