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.
View: Text | PDF
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

×

Figure 2

Deletion of SCAP in PTENΔL mice induces severe liver fibrosis and accelerates liver cancer development.

Options: View larger image (or click on image) Download as PowerPoint
Deletion of SCAP in PTENΔL mice induces severe liver fibrosis and accele...
(A) Time course of serum ALT in PTEN/SCAPΔL mice (sample sizes by age: 3 weeks, n = 2; 4 weeks, n = 5; 5 weeks, n = 8; 2 months, n = 3; 3 months, n = 3; 5 months, n = 6; 7 months, n = 6). (B) H&E, Sirius red, and oil red O staining images of livers from 5-month-old WT, PTENΔL, SCAPΔL, and PTEN/SCAPΔL mice. Scale bars: 250 μm (Sirius red); 100 μm (all others). (C) Relative expression levels of Col1a1 mRNA determined by real-time PCR in livers from mice indicated in B (n = 3 per group). (D and E) Representative liver images (D) and tumor numbers (E) for 7-month-old mice of each genotype (WT and SCAPΔL, n = 6; PTENΔL and PTEN/SCAPΔL, n = 11). Arrowheads, liver tumors. (F) H&E images of liver tumors from PTEN/SCAPΔL mice. Scale bars: 50 μm. (G) Relative expression levels of Pten and Scap mRNAs by real-time PCR in liver tissues of 7-month-old WT mice and nontumor liver tissues and tumor tissues of 7-month-old PTEN/SCAPΔL mice (WT, n = 3; nontumor and tumor tissues of PTEN/SCAPΔL mice, n = 5). (H) Immunofluorescence staining of tdTomato in HCC (left panel) and double immunofluorescence staining of tdTomato and ductal cell marker CK19 in HCC/ICC combined tumor (right panel) derived from 7-month-old PTEN/SCAPΔL;tdTomato mice. Scale bars: 100 μm. (I) Heatmaps show significant differentially expressed genes between PTENΔL tumors and PTEN/SCAPΔL tumors (PTENΔL, n = 4; PTEN/SCAPΔL, n = 5). Left panel, total differentially expressed genes. Right panel, selected differentially expressed genes. All statistical data were assessed using 1-way ANOVA with Tukey’s multiple comparison test (A, C, E, and G). Data are presented as mean ± SEM. *P < 0.05.