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The Role of Intestinal C-type Regenerating Islet Derived-3 Lectins for Nonalcoholic Steatohepatitis.

ABSTRACT: C-type regenerating islet derived-3 (Reg3) lectins defend against pathogens and keep commensal bacteria at a distance. Deficiency of Reg3g and Reg3b facilitates alcohol-induced bacterial translocation and alcoholic liver disease. Intestinal Reg3g is down-regulated in animal models of diet-induced obesity, but the functional consequences for nonalcoholic steatohepatitis (NASH) are unknown. The aim of this study was to investigate the role of Reg3 lectins in NASH. NASH was induced by a Western-style fast-food diet in mice deficient for Reg3g or Reg3b and in transgenic mice overexpressing Reg3g in intestinal epithelial cells (Reg3gTg). Glucose tolerance was assessed after 18 weeks and insulin resistance after 19 weeks of feeding. After 20 weeks, mice were assessed for features of the metabolic syndrome. Obesity was not different in genetically modified mice compared with their respective wild-type littermates. Glucose intolerance, liver injury, hepatic inflammation, steatosis, fibrosis, and bacterial translocation to mesenteric lymph nodes and to the liver were not different in Reg3g-deficient mice compared with wild-type littermates. Plasma endotoxin levels were higher in Reg3g-deficient mice. Reg3b deficiency protected against glucose intolerance, but liver disease, bacterial translocation, and plasma endotoxin levels were similar to wild-type littermates. Absence of either REG3G or REG3B protein in the ileum was not compensated for by up-regulation of the respective other REG3 protein. Transgenic Reg3g mice also developed liver injury, steatosis, and fibrosis similar to their wild-type littermates. Conclusion: In contrast to alcoholic liver disease, loss of intestinal Reg3 lectins is not sufficient to aggravate diet-induced obesity and NASH. This supports a multi-hit pathogenesis in NASH. Only glucose metabolism is affected by Reg3b deficiency. (Hepatology Communications 2018;2:393-406).

SUBMITTER: Bluemel S

PROVIDER: S-EPMC5880191 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The Role of Intestinal C-type Regenerating Islet Derived-3 Lectins for Nonalcoholic Steatohepatitis.

Bluemel Sena S Wang Lirui L Martino Cameron C Lee Suhan S Wang Yanhan Y Williams Brandon B Horvath Angela A Stadlbauer Vanessa V Zengler Karsten K Schnabl Bernd B

Hepatology communications 20180228 4

C-type regenerating islet derived-3 (Reg3) lectins defend against pathogens and keep commensal bacteria at a distance. Deficiency of Reg3g and Reg3b facilitates alcohol-induced bacterial translocation and alcoholic liver disease. Intestinal Reg3g is down-regulated in animal models of diet-induced obesity, but the functional consequences for nonalcoholic steatohepatitis (NASH) are unknown. The aim of this study was to investigate the role of Reg3 lectins in NASH. NASH was ind ...[more]

PMID: 29619418

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Project description:Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver.NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases.

Project description:Our group previously demonstrated that overexpression of selenium-dependent glutathione peroxidase-1 (GPX1) in mice (OE) led to escalated glucose-stimulated insulin secretion and hyperinsulinemia. Because we found a strong correlation of this phenotype with a diminished expression of regenerating islet-derived protein 2 (REG2) in the OE pancreatic islets, the present study was to reveal underlying mechanisms for that down-regulation of REG2 by GPX1 as a major scavenger of reactive oxygen species. We first treated the OE and wild-type (WT) mice and their islets with ROS-generating diquat, streptozotocin, and H2O2 and ROS-scavenging ebselen and N-acetylcysteine (NAC). Their effects on pancreatic and islet REG2 protein and(or) secretion were opposite (P < 0.05). Thereafter, we identified 13 transcriptional factors with putative binding sites in the Reg2 proximate promoter, and found that only activator protein-1 (AP-1) and albumin D box-binding protein (DBP) mRNA and protein levels were affected (elevated) (P < 0.05) by the GPX1 overproduction in the OE pancreatic islets compared with the WT islets. Contrary to that of Reg2 expression, their mRNA abundances in the cultured islets were elevated (P < 0.05) by ebselen and NAC, but decreased (P < 0.05) by H2O2. Both AP-1 and DBP could bind to the Reg2 promoter at the location of -168 to 0 base pair (bp) in the OE islets. Deleting the AP-1 (-143/-137 and -60/-57 bp) and(or) DBP (-35/-29 bp) binding domains in the Reg2 promoter attenuated and(or) abolished the inhibition of Reg2 promoter activation by ebselen as the GPX1 mimic in βTC-3 cells. In conclusion, the down-regulation of Reg2 expression in the GPX1-overproducing pancreatic islets was mediated by a transcriptional inhibition of the gene through two ROS responsive transcription factors AP-1 and DBP. Our findings reveal GPX1 as a novel regulator of Reg2 expression, and linking these two previously-unrelated proteins will have broad biomedical implications.

Dataset Information

The Role of Intestinal C-type Regenerating Islet Derived-3 Lectins for Nonalcoholic Steatohepatitis.

Publications

The Role of Intestinal C-type Regenerating Islet Derived-3 Lectins for Nonalcoholic Steatohepatitis.

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