glucagon-like-peptide-1 and Choline-Deficiency

Non-alcoholic steatohepatitis (NASH) is characterized by a robust pro-inflammatory component at both hepatic and systemic levels together with a disease-specific gut microbiome signature. Protein tyrosine phosphatase 1 B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory signaling cascades. In this study, we have explored the role of PTP1B in the composition of gut microbiota and gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice.. Gut features and barrier permeability were characterized in wild-type (PTP1B WT) and PTP1B-deficient knockout (PTP1B KO) mice fed a chow or methionine/choline-deficient (MCD) diet for 4 weeks. The impact of inflammation was studied in intestinal epithelial and enteroendocrine cells. The secretion of GLP-1 was evaluated in primary colonic cultures and plasma of mice.. We found that a shift in the gut microbiota shape, disruption of gut barrier function, higher levels of serum bile acids, and decreased circulating glucagon-like peptide (GLP)-1 are features during NASH. Surprisingly, despite the pro-inflammatory phenotype of global PTP1B-deficient mice, they were partly protected against the alterations in gut microbiota composition during NASH and presented better gut barrier integrity and less permeability under this pathological condition. These effects concurred with higher colonic mucosal inflammation, decreased serum bile acids, and protection against the decrease in circulating GLP-1 levels during NASH compared with their WT counterparts together with increased expression of GLP-2-sensitive genes in the gut. At the molecular level, stimulation of enteroendocrine STC-1 cells with a pro-inflammatory conditioned medium (CM) from lipopolysaccharide (LPS)-stimulated macrophages triggered pro-inflammatory signaling cascades that were further exacerbated by a PTP1B inhibitor. Likewise, the pro-inflammatory CM induced GLP-1 secretion in primary colonic cultures, an effect augmented by PTP1B inhibition.. Altogether our results have unraveled a potential role of PTP1B in the gut-liver axis during NASH, likely mediated by increased sensitivity to GLPs, with potential therapeutic value.

Topics: Animals; Choline Deficiency; Diet; Disease Models, Animal; Gastrointestinal Microbiome; Gene Expression; Gene Knockout Techniques; Glucagon-Like Peptide 1; Inflammation; Intestinal Mucosa; Liver; Male; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Permeability; Protein Tyrosine Phosphatase, Non-Receptor Type 1; RAW 264.7 Cells

Several lines of evidence have suggested a role of gut microbiota in the etiology of nonalcoholic steatohepatitis (NASH). NASH subjects reportedly showed a prolonged orocecal transit time coexistent with small intestinal bacterial overgrowth. We considered the possibility that enhanced gastrointestinal motility would influence gut microbiota and thus investigated the effects of the gastroprokinetic agent mosapride citrate (MC) on gut microbiota and the development of NASH using a methionine-choline deficient (MCD) diet-fed rodent model. Mice were divided into three groups, given the normal chow diet (NCD), the MCD diet, or the MCD diet containing 10 mg·kg(-1)·day(-1) of MC (MCD plus MC) for 6 wk. NASH development was evaluated based on hepatic histochemical findings, serum parameters and various mRNA and/or protein expression levels. MC treatment suppressed MCD diet-induced NASH development, with reduced serum lipopolysaccharide and increased plasma glucagon-like peptide-1 (GLP-1) concentrations. Calculation of the relative abundance of each strain based on gut microbiota analyses indicated lactic acid bacteria specifically, such as Bifidobacterium and Lactobacillus, in feces to be decreased in the MCD, compared with the NCD group. Interestingly, the reduction in lactic acid bacteria in the MCD diet group was reversed in the MCD plus MC group. In addition, colon inflammation observed in the MCD diet group was reduced in the MCD plus MC group. Therefore, MC showed a protective effect against MCD diet-induced NASH development in our rodent model, with possible involvements of increased fecal lactic acid bacteria, protection against colon inflammation and elevated plasma GLP-1.

Topics: Animals; Benzamides; Choline Deficiency; Feces; Gastrointestinal Tract; Glucagon-Like Peptide 1; Inflammation; Lactic Acid; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Morpholines; Non-alcoholic Fatty Liver Disease

GATA4, a zinc finger domain transcription factor, is critical for jejunal identity. Mice with an intestine-specific GATA4 deficiency (GATA4iKO) are resistant to diet-induced obesity and insulin resistance. Although they have decreased intestinal lipid absorption, hepatic de novo lipogenesis is inhibited. Here, we investigated dietary lipid-dependent and independent effects on the development of steatosis and fibrosis in GATA4iKO mice.. GATA4iKO and control mice were fed a Western-type diet (WTD) or a methionine and choline-deficient diet (MCDD) for 20 and 3 weeks, respectively. Functional effects of GATA4iKO on diet-induced liver steatosis were investigated.. WTD-but not MCDD-fed GATA4iKO mice showed lower hepatic concentrations of triglycerides, free fatty acids, and thiobarbituric acid reactive species and had reduced expression of lipogenic as well as fibrotic genes compared with controls. Reduced nuclear sterol regulatory element-binding protein-1c protein levels were accompanied by lower lipogenic gene expression. Oil red O and Sirius Red staining of liver sections confirmed the observed reduction in hepatic lipid accumulation and fibrosis. Immunohistochemical staining revealed an increased number of jejunal glucagon-like peptide 1 (GLP-1) positive cells in GATA4iKO mice. Consequently, we found enhanced phosphorylation of hepatic AMP-activated protein kinase and acetyl-CoA carboxylase alpha.. Our results provide strong indications for a protective effect of intestinal GATA4 deficiency on the development of hepatic steatosis and fibrosis via GLP-1, thereby blocking hepatic de novo lipogenesis.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Choline Deficiency; Diet; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; GATA4 Transcription Factor; Glucagon-Like Peptide 1; Jejunum; Lipid Metabolism; Liver Cirrhosis; Male; Methionine; Mice; Mice, Knockout; Protein Kinases; Sterol Regulatory Element Binding Protein 1; Thiobarbituric Acid Reactive Substances; Triglycerides