alpha-Tocopherol supplementation reduces inflammation and apoptosis in high cholesterol mediated nonalcoholic steatohepatitis

Abstract

Inflammation and apoptosis signaling are crucial steps in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Alpha-tocopherol, the most active form of vitamin E, is an important modulator of signaling mechanisms, but its involvement to cholesterol-induced NASH pathogenesis remains poorly defined. Herein we have reported a novel effect of alpha-tocopherol in the transition from hepatic steatosis to NASH. High cholesterol diet alone (without alpha-tocopherol) in rabbits elevated NASH development as indicated by increased inflammatory response, apoptotic activity and liver fibrosis. Such elevation results from induction of signaling mechanisms since the expressions of IL1 beta, phospho c-Jun/c-Jun ratio, JNK, caspase 9, CHOP and Bax were increased, and recruitment of macrophage, alpha-smooth muscle actin (alpha-SMA) and COL1A1 into the liver tissue were induced. Alpha-tocopherol supplementation inhibited inflammatory response, apoptosis and fibrosis development without affecting lipid accumulation in high cholesterol-induced NASH. Specifically, alpha-tocopherol lowered the inflammatory level as observed by reduced macrophage infiltration and JNK/c-Jun signaling. Lower inflammatory status co-occurred with the reduction of CHOP and Bax expressions as well as fibrosis-related COL1A1 and alpha-SMA levels. Taken together, alpha-tocopherol supplementation inhibits cholesterol-induced NASH development by lowering JNK/c-Jun/inflammation axis in addition to JNK/CHOP/apoptosis signaling, which might contribute to resistance against NAFLD/NASH transition.