Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

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 p...

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Published in:The Journal of clinical investigation 2015-12, Vol.125 (12), p.4447-4462
Main Authors: Satapati, Santhosh, Kucejova, Blanka, Duarte, Joao A G, Fletcher, Justin A, Reynolds, Lacy, Sunny, Nishanth E, He, Tianteng, Nair, L Arya, Livingston, Kenneth A, Livingston, Kenneth, Fu, Xiaorong, Merritt, Matthew E, Sherry, A Dean, Malloy, Craig R, Shelton, John M, Lambert, Jennifer, Parks, Elizabeth J, Corbin, Ian, Magnuson, Mark A, Browning, Jeffrey D, Burgess, Shawn C
Format: Article
Language:English
Subjects:
Animals
Biomedical research
Biopsy
Cell metabolism
Development and progression
Diabetes
Experiments
Genetic aspects
Health aspects
Hepatocytes - metabolism
Hepatocytes - pathology
Humans
Inflammation
Inflammation - metabolism
Inflammation - pathology
Insulin
Insulin resistance
Intracellular Signaling Peptides and Proteins - metabolism
Liver
Liver diseases
Metabolism
Metabolites
Mice
Mitochondria
Mitochondria, Liver - metabolism
Mitochondria, Liver - pathology
Non-alcoholic Fatty Liver Disease - metabolism
Non-alcoholic Fatty Liver Disease - pathology
Oxidation
Oxidative Stress
Phosphoenolpyruvate Carboxykinase (GTP) - metabolism
Rats
Rats, Wistar
Respiration
Rodents
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci82204