Journal Article

Caspase-1 as a Central Regulator of High Fat Diet-Induced Non-Alcoholic Steatohepatitis

Dixon, Laura J., Feldstein, Ariel E., Nagy, Laura E., Papouchado, Bettina G., Flask, Chris A.

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adiposity / Animals / Apoptosis / Biology / Biomarkers - metabolism / Caspase / Caspase 1 - deficiency / Caspase 1 - genetics / Caspase 1 - metabolism / Caspase-1 / Chemokines / Cholesterol / Cytokines / Development and progression / Diet / Diet, High-Fat - adverse effects / Enzymes / Fatty acids / Fatty liver / Fatty Liver - enzymology / Fatty Liver - etiology / Fatty Liver - genetics / Fatty Liver - pathology / Fibrosis / Gastroenterology / Gene expression / Gene Expression Regulation, Enzymologic / Gene Knockout Techniques / Genes / Hepatology / High fat diet / House mouse / Hypotheses / IL-1β / Inflammasomes / Inflammation / Insulin resistance / Interleukin-1beta - genetics / Lipids / Lipogenesis / Liver / Liver - metabolism / Liver - pathology / Liver cancer / Liver diseases / Male / Medicine / Mice / Mice, Inbred C57BL / Monocyte chemoattractant protein 1 / Obesity / Obesity - enzymology / Obesity - etiology / Obesity - genetics / Obesity - pathology / Oxidation / Pathogenesis / Physiology / Proteins / RNA / Rodents / Steatosis / Weight control