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Ablation of Hmgb1 in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice.

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a metabolic disorder in which poor nutrition and the gut-to-liver interaction play a major role. We previously established that hepatic high mobility group box-1 (HMGB1) is involved in chronic liver disease. HMGB1 increases in patients with NASH and it is expressed in intestinal epithelial cells (IEC); yet, the role of intestinal HMGB1 in the pathogenesis of NASH has not been investigated. Thus, we hypothesized that IEC-derived HMGB1 could play a role in NASH due to local effects in the intestine that govern hepatic steatosis. Control littermates and Hmgb1 ?IEC mice were fed for 1 or 24 weeks a control diet or a high fat, high cholesterol (CHO) and fructose-enriched diet (HFCFD). Hepatic and intestinal injury were analyzed. Hmgb1 ?IEC mice were protected from HFCFD-induced NASH after 1 or 24 weeks of feeding; however, they showed extensive atypical lipid droplet accumulation and increased concentrations of triglycerides (TG) and CHO in jejunal IEC together with lower TG and other lipid classes in serum. Olive oil or CHO gavage resulted in decreased serum TG and CHO in Hmgb1 ?IEC mice, respectively, indicating delayed and/or reduced chylomicron (CM) efflux. There was significant up-regulation of scavenger receptor class B type 1 (SR-B1) and down-regulation of apolipoprotein B48 (ApoB48) proteins, suggesting decreased lipid packaging and/or CM formation that resulted in lesser hepatosteatosis. Conclusion: Ablation of Hmgb1 in IEC causes up-regulation of SR-B1 and down-regulation of ApoB48, leads to lipid accumulation in jejunal IEC, decreases CM packaging and/or release, reduces serum TG, and lessens liver steatosis, therefore protecting Hmgb1 ?IEC mice from HFCFD-induced NASH.

SUBMITTER: Gaskell H

PROVIDER: S-EPMC6939545 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Ablation of <i>Hmgb1</i> in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice.

Gaskell Harriet H Ge Xiaodong X Desert Romain R Das Sukanta S Han Hui H Lantvit Daniel D Guzman Grace G Nieto Natalia N

Hepatology communications 20191112 1

Nonalcoholic steatohepatitis (NASH) is a metabolic disorder in which poor nutrition and the gut-to-liver interaction play a major role. We previously established that hepatic high mobility group box-1 (HMGB1) is involved in chronic liver disease. HMGB1 increases in patients with NASH and it is expressed in intestinal epithelial cells (IEC); yet, the role of intestinal HMGB1 in the pathogenesis of NASH has not been investigated. Thus, we hypothesized that IEC-derived HMGB1 could play a role in NA ...[more]

PMID: 31909358

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Project description:Background & aimsThe lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in Sprague-Dawley rats with steatosis. However, the individual roles of extracellular and intracellular CTSD in NASH are not yet known. In the current study, we evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors.MethodsLow-density lipoprotein receptor knock out (Ldlr-/-) mice were fed a high-fat, high cholesterol (HFC) diet for ten weeks to induce NASH. Further, to investigate the effects of CTSD inhibition, mice were injected either with an intracellular (GA-12) or extracellular (CTD-002) CTSD inhibitor or vehicle control at doses of 50 mg/kg body weight subcutaneously once in two days for ten weeks.ResultsLdlr-/- mice treated with extracellular CTSD inhibitor showed reduced hepatic lipid accumulation and an associated increase in faecal bile acid levels as compared to intracellular CTSD inhibitor-treated mice. Furthermore, in contrast to intracellular CTSD inhibition, extracellular CTSD inhibition switched the systemic immune status of the mice to an anti-inflammatory profile. In line, label-free mass spectrometry-based proteomics revealed that extra- and intracellular CTSD fractions modulate proteins belonging to distinct metabolic pathways.ConclusionWe have provided clinically translatable evidence that extracellular CTSD inhibition shows some beneficial metabolic and systemic inflammatory effects which are distinct from intracellular CTSD inhibition. Considering that intracellular CTSD inhibition is involved in essential physiological processes, specific inhibitors capable of blocking extracellular CTSD activity, can be promising and safe NASH drugs.

Project description:BACKGROUND & AIMS:NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. METHODS:We fed foz/foz and wild-type mice an atherogenic diet for 16weeks, gavaged MCC950 or vehicle until 24weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6weeks and determined the effects on liver fibrosis. RESULTS:In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1?, active caspase-1 and IL-1? increased at 24weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1?, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1? expression, plasma IL-1?, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1?; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1?, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. CONCLUSION:MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. LAY SUMMARY:Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation in NASH, but activation of a protein scaffold within cells termed the inflammasome (NLRP3) has been suggested to play a role. Here we show that cholesterol crystals could be one pathway to activate the inflammasome in NASH. We used a drug called MCC950, which has already been shown to block NLRP3 activation, in an attempt to reduce liver injury in NASH. This drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resembles the human context of NASH. In addition, such dampening of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to the development of cirrhosis.

Dataset Information

Ablation of Hmgb1 in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice.

Publications

Ablation of <i>Hmgb1</i> in Intestinal Epithelial Cells Causes Intestinal Lipid Accumulation and Reduces NASH in Mice.

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