Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver.

Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L, Sunny NE, He T, Nair LA, Livingston KA, Livingston K, Fu X, Merritt ME, Sherry AD, Malloy CR, Shelton JM, Lambert J, Parks EJ, Corbin I, Magnuson MA, Browning JD, Burgess SC
J Clin Invest. 2015 125 (12): 4447-62

PMID: 26571396 · PMCID: PMC4665800 · DOI:10.1172/JCI82204

Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid-induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways.

MeSH Terms (12)

Animals Hepatocytes Humans Inflammation Intracellular Signaling Peptides and Proteins Mice Mitochondria, Liver Non-alcoholic Fatty Liver Disease Oxidative Stress Phosphoenolpyruvate Carboxykinase (GTP) Rats Rats, Wistar

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