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



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).



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.



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.
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.|Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Top Institute Food and Nutrition, Nieuwe Kanaal 9A, Wageningen, The Netherlands.
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Morrison
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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0000-0002-0982-4466
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Mulder
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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Salic
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Verheij
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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Liang
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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van Duyvenvoorde
TNO Triskelion, Zeist, The Netherlands.
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A
Menke
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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T
Kooistra
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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Kleemann
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Leiden, The Netherlands.
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Wielinga
D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications / Q000209:etiology / Q000378:metabolism; D006946:Hyperinsulinism / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007333:Insulin Resistance; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology / Q000627:therapeutic use*; D014764:Viral Proteins / Q000494:pharmacology / Q000627:therapeutic use*
D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor