Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease

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Luukkonen , P K , Dufour , S , Lyu , K , Zhang , X-M , Hakkarainen , A , Lehtimäki , T E , Cline , G W , Petersen , K F , Shulman , G I & Yki-Järvinen , H 2020 , ' Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 117 , no. 13 , pp. 7347-7354 . https://doi.org/10.1073/pnas.1922344117

Title: Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease
Author: Luukkonen, Panu K.; Dufour, Sylvie; Lyu, Kun; Zhang, Xian-Man; Hakkarainen, Antti; Lehtimäki, Tiina E.; Cline, Gary W.; Petersen, Kitt Falk; Shulman, Gerald I.; Yki-Järvinen, Hannele
Contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, HUS Medical Imaging Center
University of Helsinki, Department of Diagnostics and Therapeutics
University of Helsinki, Department of Medicine
Date: 2020-03-31
Language: eng
Number of pages: 8
Belongs to series: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
URI: http://hdl.handle.net/10138/314457
Abstract: Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D-7]glucose, [C-13(4)]beta-hydroxybutyrate and [3-C-13]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (H-1-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (-58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward keto-genesis (+232%) due to reductions in serum insulin concentrations (-53%) and hepatic citrate synthase flux (-38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (-45%) and triiodothyronine (-21%) concentrations. These data demonstrate heretofore unde-scribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.
Subject: 3111 Biomedicine
carbohydrate restriction
redox
citrate synthase
insulin resistance
pyruvate carboxylase
LOW-CARBOHYDRATE DIET
DE-NOVO LIPOGENESIS
INSULIN-RESISTANCE
WEIGHT-LOSS
ADIPOSE-TISSUE
TRIGLYCERIDE CONTENT
REDOX STATE
SPECTROSCOPY
CYCLE
ACIDS
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