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Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity
Thomas Grenier-Larouche, … , Christopher B. Newgard, Phillip J. White
Thomas Grenier-Larouche, … , Christopher B. Newgard, Phillip J. White
Published July 7, 2022
Citation Information: JCI Insight. 2022;7(15):e159204. https://doi.org/10.1172/jci.insight.159204.
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Research Article Hepatology Metabolism

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity

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Abstract

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

Authors

Thomas Grenier-Larouche, Lydia Coulter Kwee, Yann Deleye, Paola Leon-Mimila, Jacquelyn M. Walejko, Robert W. McGarrah, Simon Marceau, Sylvain Trahan, Christine Racine, André C. Carpentier, Aldons J. Lusis, Olga Ilkayeva, Marie-Claude Vohl, Adriana Huertas-Vazquez, André Tchernof, Svati H. Shah, Christopher B. Newgard, Phillip J. White

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Figure 1

Regulation of BCKDK expression by SREBP1.

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Regulation of BCKDK expression by SREBP1.
(A) H3K27Ac peaks (multicolore...
(A) H3K27Ac peaks (multicolored) and SREBP1 ChIP-Seq data (pink) in the promoter and upstream enhancer region of the BCKDK gene. Conservation of these genomic regions relative to the human genome is indicated by vertical black hatch marks to the right of each mammal. (B) Correlation between BCKDK and SREBP1 gene expression in liver samples from the Mexican Obesity Surgery cohort. (C and D) The effect of the SREBP1 inhibitors, Betulin and PF-429242, on FASN and BCKDK mRNA expression in AML12 cells. Data are expressed as the mean ± SEM of 3 independent experiments. A 1-way ANOVA with a Dunnett’s post hoc test was employed to determine statistical significance. ****P < 0.001.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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