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

Panu K. Luukkonen, Sylvie Dufour, Kun Lyu, Xian Man Zhang, Antti Hakkarainen, Tiina E. Lehtimäki, Gary W. Cline, Kitt Falk Petersen, Gerald I. Shulman*, Hannele Yki-Järvinen

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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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: [D7]glucose, [13C4]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (1H-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 ketogenesis (+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 undescribed 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.

Original languageEnglish
Pages (from-to)7347-7354
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number13
DOIs
Publication statusPublished - 31 Mar 2020
MoE publication typeA1 Journal article-refereed

Keywords

  • Carbohydrate restriction
  • Citrate synthase
  • Insulin resistance
  • Pyruvate carboxylase
  • Redox

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