Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver
Santhosh Satapati, Blanka Kucejova, Joao A.G. Duarte, Justin A. Fletcher, Lacy Reynolds, Nishanth E. Sunny, Tianteng He, L. Arya Nair, Kenneth Livingston, Xiaorong Fu, Matthew E. Merritt, A. Dean Sherry, Craig R. Malloy, John M. Shelton, Jennifer Lambert, Elizabeth J. Parks, Ian Corbin, Mark A. Magnuson, Jeffrey D. Browning, Shawn C. Burgess
Santhosh Satapati, Blanka Kucejova, Joao A.G. Duarte, Justin A. Fletcher, Lacy Reynolds, Nishanth E. Sunny, Tianteng He, L. Arya Nair, Kenneth Livingston, Xiaorong Fu, Matthew E. Merritt, A. Dean Sherry, Craig R. Malloy, John M. Shelton, Jennifer Lambert, Elizabeth J. Parks, Ian Corbin, Mark A. Magnuson, Jeffrey D. Browning, Shawn C. Burgess
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Research Article Metabolism

Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

Abstract

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.

Authors

Santhosh Satapati, Blanka Kucejova, Joao A.G. Duarte, Justin A. Fletcher, Lacy Reynolds, Nishanth E. Sunny, Tianteng He, L. Arya Nair, Kenneth Livingston, Xiaorong Fu, Matthew E. Merritt, A. Dean Sherry, Craig R. Malloy, John M. Shelton, Jennifer Lambert, Elizabeth J. Parks, Ian Corbin, Mark A. Magnuson, Jeffrey D. Browning, Shawn C. Burgess

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Figure 3

The induction of oxidative metabolism by NEFA requires increased anaplerosis/cataplerosis to cause oxidative stress and inflammation.

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The induction of oxidative metabolism by NEFA requires increased anapler...
Increasing circulating NEFA by intralipid infusion (n = 4–6) caused a rise in fat oxidation indicated by a rise in (A) ketogenesis and TCA cycle flux and (B) GNG and anaplerosis measured by tracer methods. (C) Calculated oxygen consumption was increased by intralipid infusion in proportion to the rise in circulating NEFA. Oxidative stress, as indicated by (D) Sod2 mRNA and (E) lipid peroxidation, increased in proportion to the rise in oxygen consumption. The inflammatory response, as indicated by (F) Tnfa and (G) Il6 mRNA, was elevated by NEFA in proportion to the rise in oxygen consumption. (H) Administration of an inhibitor of PEPCK, 100 μM mercaptopicolinate, blocked the induction of ROS in H4IIE rat hepatoma cells treated with high NEFA (n = 3). Data are shown as mean ± SEM. Statistical differences were detected by 2-tailed t tests, except for H, which used a 2-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001.