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 6

SREBP dysfunction–mediated downregulation of LPCAT3 is associated with ER stress.

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SREBP dysfunction–mediated downregulation of LPCAT3 is associated with E...
(A) FA composition of PCs in 5-week-old PTEN/SCAPΔL and PTEN/SCAPΔL;S1aTg mouse livers (n = 3 per group). (B and C) Relative expression levels of LPCAT family members determined by RNA-Seq (B) and real-time PCR (C) in 5-week-old mice of each genotype (n = 6 per group). (D) Relative expression levels of LPCAT family members in 5-week-old mice of each genotype by real-time PCR (n = 3 per group). (E) Expression levels of indicated proteins determined by WB. (F) Ptenfl/fl/Scapfl/fl hepatocytes were infected with Ad-Cont or Ad-Cre. At 96 hours, expression levels of Lpcat3 were determined by real-time PCR (n = 3 per group). (G) Primary hepatocytes from PTEN/SCAPΔL mice were infected with Ad-Cont (MOI = 30) or Ad-LPCAT3 at indicated MOI. At 96 hours, p-eIF2α expression levels were determined by WB. Experiments were performed in medium containing normal FBS (left) or moderately delipidated FBS (30% lipid) (right). (H) Relative expression levels of indicated genes in livers from 5-week-old mice of each genotype by real-time PCR (n = 6 per group). (I) Expression levels of indicated genes by real-time PCR (n = 3 per group). (J) Relative expression levels of LXR target genes in hepatocytes indicated in F by real-time PCR (n = 3 per group). (K) PTEN/SCAPΔL hepatocytes were treated with 5 μM GW3965 or vehicle. At 48 hours, expression levels of indicated genes were analyzed by real-time PCR (n = 6 per group). Statistical data were assessed using Student’s t test (A, F, J and K) and 1-way ANOVA with Tukey’s multiple comparisons test (C, D, H, and I). Data are presented as mean ± SEM. *P < 0.05.