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Involvement of resistin-like molecule ? in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

ABSTRACT: Resistin-like molecule ? (RELM?) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELM? to non-alcoholic steatohepatitis (NASH) development. First, RELM? knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELM? and that RELM? expression levels in the colon and the numbers of RELM?-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELM?-KO mice to distinguish between the contributions of RELM? in these two organs. These experiments revealed the requirement of RELM? in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELM?-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELM? in the gut and Kupffer cells to NASH development, raising the possibility of RELM? being a novel therapeutic target for NASH.

SUBMITTER: Okubo H

PROVIDER: S-EPMC4730188 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

Okubo Hirofumi H Kushiyama Akifumi A Sakoda Hideyuki H Nakatsu Yusuke Y Iizuka Masaki M Taki Naoyuki N Fujishiro Midori M Fukushima Toshiaki T Kamata Hideaki H Nagamachi Akiko A Inaba Toshiya T Nishimura Fusanori F Katagiri Hideki H Asahara Takashi T Yoshida Yasuto Y Chonan Osamu O Encinas Jeffery J Asano Tomoichiro T

Scientific reports 20160128

Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of R ...[more]

PMID: 26818807

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Project description:BackgroundPhosphoglycerate mutase 5 (PGAM5), a phosphatase involved in mitochondrial homeostasis, is reported to be closely related to the metabolic stress induced by high-fat diet (HFD) or cold. In this study, we aimed to investigate the effects of PGAM5 on hepatic steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH).Methods and resultsWe generated PGAM5 global knockout (GKO) mice and their wildtype (WT) littermates using CRISPR/CAS9. The mice were fed with a high fat high fructose (HFHF) diet for 12 weeks or a methionine choline-deficient (MCD) diet (methionine choline supplemented (MCS) as control) for 6 weeks. Hepatic PGAM5 expression was up-regulated in humans with NASH and WT mice fed with HFHF and MCS, and reduced in WT mice fed with MCD diet. In HFHF-fed mice, GKO had reduced body weight, hepatic triglyceride (TG) content and serum transaminase along with decreased hepatic pro-inflammatory and pro-fibrotic responses compared with their WT control. GKO had increased expression of antioxidative gene glutathione peroxidase-6 (GPX6) and activation of mammalian target of rapamycin (mTOR). In mice fed with MCS diet, GKO significantly increased serum TNF-α and IL-6 and decreased hepatic GPX6 mRNA expression. There was no difference in hepatic steatosis, inflammation or fibrosis between GKO and WT mice fed with MCD diet. We investigated the role of PGAM5 deficiency in a variety of cell types. In differentiated THP-1 cells, PGAM5 silencing significantly increased pro-inflammatory cytokine secretion and decreased antioxidative proteins, including nuclear factor erythroid 2- related factors (NRF2), heme oxygenase-1 (HO-1) and GPX6 without affecting mTOR activity. In HepG2 cells with steatosis, PGAM5 knockdown reduced insulin sensitivity, increased mTOR phosphorylation and reduced the expression of NRF2, catalase (CAT), HO-1 and GPX6. Conversely, PGAM5 knockdown reduced TG accumulation, increased insulin sensitivity, and increased antioxidative genes in 3T3-L1 cells, despite the up-regulation in mTOR phosphorylation.ConclusionsPGAM5-KO relieved hepatic steatosis and inflammation in HFHF model, promoted inflammation in MCS-fed mice and had no effects on the MCD-fed model. The distinct effects may be owing to the different effects of PGAM5-KO on anti-oxidative pathways in energy-dependent, possible involves mTOR, and/or cell type-dependent manner. Our findings suggest that PGAM5 can be a potential therapeutic target for NASH.

Dataset Information

Involvement of resistin-like molecule ? in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

Publications

Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

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