Title
Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis in LDLR-/-.Leiden mice
Author
Morrison, M.C.
Mulder, P.
Salic, K.
Verheij, J.
Liang, W.
van Duyvenvoorde, W.
Menke, A.
Kooistra, T.
Kleemann, R.
Wielinga, P.Y.
Publication year
2016
Abstract
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/day). Results: 9 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 dyslipidaemia, 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
Subject
ELSS - Earth, Life and Social Sciences
Life
Healthy Living
Biomedical Innovation
Biology
MHR - Metabolic Health Research
To reference this document use:
http://resolver.tudelft.nl/uuid:5403de4f-55b0-4f25-96f4-fa3681985411
DOI
https://doi.org/10.1038/ijo.2016.74
TNO identifier
536658
Source
International Journal of Obesity, 40 (40), 1416-1423
Document type
article