Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis and hepatic fibrosis in LDLR−/−.Leiden mice

• Published in: International Journal of Obesity 2016-09, Vol.40 (9), p.1416-1423
• Main Authors: Morrison, M C, Mulder, P, Salic, K, Verheij, J, Liang, W, van Duyvenvoorde, W, Menke, A, Kooistra, T, Kleemann, R, Wielinga, P Y
• Format: Article
• Language: English
• Subjects: 38/77; 64/60; 692/163/2743/393; 692/308; 692/420/256/2177; 692/699; 692/699/1503/1607/2751; 692/700/565; Analysis; Animals; Body weight; Diabetes; Diet; Diet, High-Fat; Disease Models, Animal; Dyslipidemias - complications; Dyslipidemias - etiology; Dyslipidemias - metabolism; Epidemiology; Fibrosis; Gene expression; Health aspects; Health Promotion and Disease Prevention; Hypercholesterolemia; Hyperinsulinism - complications; Hyperinsulinism - drug therapy; Hyperinsulinism - pathology; Insulin Resistance; Internal Medicine; Liver; Liver Cirrhosis - complications; Liver Cirrhosis - drug therapy; Liver Cirrhosis - pathology; Liver diseases; Male; Medical research; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - pathology; Nutrition research; Obesity; Obesity - complications; Obesity - etiology; Obesity - metabolism; Original; original-article; Prediabetic state; Public Health; Serpins - pharmacology; Serpins - therapeutic use; Type 2 diabetes; Viral Proteins - pharmacology; Viral Proteins - therapeutic use
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2016.74

Background/Objectives: Non-alcoholic steatohepatitis (NASH) is a serious liver condition, closely associated with obesity and insulin resistance. Recent studies have suggested an important role for inflammasome/caspase-1 in the development of NASH, but the potential therapeutic value of caspase-1 inhibition remains unclear. Therefore, we aimed to investigate the effects of caspase-1 inhibition in the ongoing disease process, to mimic the clinical setting. Subjects/Methods: To investigate effects of caspase-1 inhibition under therapeutic conditions, male LDLR−/−.Leiden mice were fed a high-fat diet (HFD) for 9 weeks to induce a pre-diabetic state before start of treatment. Mice were then continued on HFD for another 12 weeks, without (HFD) or with (HFD-YVAD) treatment with the caspase-1 inhibitor Ac-YVAD-cmk (40 mg kg −1 per day). Results: Nine weeks of HFD feeding resulted in an obese phenotype, with obesity-associated hypertriglyceridemia, hypercholesterolemia, hyperglycemia and hyperinsulinemia. Treatment with Ac-YVAD-cmk did not affect further body weight gain or dyslipidemia, but did attenuate further progression of insulin resistance. Histopathological analysis of livers clearly demonstrated prevention of NASH development in HFD-YVAD mice: livers were less steatotic and neutrophil infiltration was strongly reduced. In addition, caspase-1 inhibition had a profound effect on hepatic fibrosis, as assessed by histological quantification of collagen staining and gene expression analysis of fibrosis-associated genes Col1a1, Acta2 and Tnfa . Conclusions: Intervention with a caspase-1 inhibitor attenuated the development of NASH, liver fibrosis and insulin resistance. Our data support the importance of inflammasome/caspase-1 in the development of NASH and demonstrate that therapeutic intervention in the already ongoing disease process is feasible.