Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis
Satoshi Kawamura, … , Kazuhiko Koike, Hayato Nakagawa
Satoshi Kawamura, … , Kazuhiko Koike, Hayato Nakagawa
Published April 5, 2022
Citation Information: J Clin Invest. 2022;132(11):e151895. https://doi.org/10.1172/JCI151895.
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Research Article Gastroenterology

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.

Authors

Satoshi Kawamura, Yuki Matsushita, Shigeyuki Kurosaki, Mizuki Tange, Naoto Fujiwara, Yuki Hayata, Yoku Hayakawa, Nobumi Suzuki, Masahiro Hata, Mayo Tsuboi, Takahiro Kishikawa, Hiroto Kinoshita, Takuma Nakatsuka, Masaya Sato, Yotaro Kudo, Yujin Hoshida, Atsushi Umemura, Akiko Eguchi, Tsuneo Ikenoue, Yoshihiro Hirata, Motonari Uesugi, Ryosuke Tateishi, Keisuke Tateishi, Mitsuhiro Fujishiro, Kazuhiko Koike, Hayato Nakagawa

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Figure 1

Liver-specific PTEN/SCAP double-knockout mice exhibit severe liver injury.

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Liver-specific PTEN/SCAP double-knockout mice exhibit severe liver injur...
(A) Serum levels of ALT, ALP, total bilirubin, and liver weight in 5-week-old WT, PTENΔL, SCAPΔL, and PTEN/SCAPΔL mice (n = 6 per group). (B and C) H&E (B) and oil red O (C) staining images of livers from mice indicated in A. Right H&E image shows the focal necrosis of liver parenchyma in PTEN/SCAPΔL mice. Scale bars: 50 μm (H&E, furthest right); 100 μm (all others). (D) IHC images of indicated proteins in livers from mice indicated in A. Scale bars: 100 μm. Red arrowheads, Ki67-expressing hepatocytes; yellow arrowheads, hepatocytes expressing SREBP-1 in the cytoplasm but not the nucleus. Enlarged high magnification images of Ki67 and SREBP-1 staining are shown in Supplemental Figure 1B. (E) Cytoplasmic and nuclear protein fractions were extracted from 5-week-old PTENΔL and PTEN/SCAPΔL mouse livers, and the cytoplasmic protein levels of precursor SREBP-1 (p-SREBP1) and nuclear mature form of SREBP-1 (m-SREBP1) were analyzed by WB. (F) WB analyses of indicated proteins in livers from mice indicated in A. (G) Relative expression levels of lipogenic genes determined by real-time PCR in livers from mice indicated in A (n = 6 per group). *P < 0.05. (H) Hepatic TG and total cholesterol content of livers from mice indicated in A (n = 3 per group). (I) Relative expression levels of inflammatory cytokines determined by real-time PCR in livers from mice indicated in A (n = 6 per group). *P < 0.05. All statistical data were assessed using 1-way ANOVA with Tukey’s multiple comparison test (A, G, H, and I) and are presented as mean ± SEM.