title: Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis.
abstract: Nonalcoholic steatohepatitis (NASH) is associated with caspase activation. However, a role for pro-inflammatory caspases or inflammasomes has not been explored in diet-induced liver injury. Our aims were to examine the role of caspase-1 in high fat-induced NASH. C57BL/6 wild-type and caspase 1-knockout (Casp1(-/-)) mice were placed on a 12-week high fat diet. Wild-type mice on the high fat diet increased hepatic expression of pro-caspase-1 and IL-1β. Both wild-type and Casp1(-/-) mice on the high fat diet gained more weight than mice on a control diet. Hepatic steatosis and TG levels were increased in wild-type mice on high fat diet, but were attenuated in the absence of caspase-1. Plasma cholesterol and free fatty acids were elevated in wild-type, but not Casp1(-/-) mice, on high fat diet. ALT levels were elevated in both wild-type and Casp1(-/-) mice on high fat diet compared to control. Hepatic mRNA expression for genes associated with lipogenesis was lower in Casp1(-/-) mice on high fat diet compared to wild-type mice on high fat diet, while genes associated with fatty acid oxidation were not affected by diet or genotype. Hepatic Tnfα and Mcp-1 mRNA expression was increased in wild-type mice on high fat diet, but not in Casp1(-/-) mice on high fat diet. αSMA positive cells, Sirius red staining, and Col1α1 mRNA were increased in wild-type mice on high fat diet compared to control. Deficiency of caspase-1 prevented those increases. In summary, the absence of caspase-1 ameliorates the injurious effects of high fat diet-induced obesity on the liver. Specifically, mice deficient in caspase-1 are protected from high fat-induced hepatic steatosis, inflammation and early fibrogenesis. These data point to the inflammasome as an important therapeutic target for NASH.
authors: Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Laura J
authors: LJ
authors: Dixon
authors: Chris A
authors: CA
authors: Flask
authors: Bettina G
authors: BG
authors: Papouchado
authors: Ariel E
authors: AE
authors: Feldstein
authors: Laura E
authors: LE
authors: Nagy
mesh_terms: D050154:Adiposity; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D053583:Interleukin-1beta / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology
chemical_list: D015415:Biomarkers; D053583:Interleukin-1beta; D020170:Caspase 1