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9-HODE and 9-HOTrE alter mitochondrial metabolism, increase triglycerides, and perturb fatty acid uptake and synthesis associated gene expression in HepG2 cells.
Evans, William A; Eccles-Miller, Jazmine A; Anderson, Eleanor; Farrell, Hannah; Baldwin, William S.
Afiliação
  • Evans WA; Clemson University, Biological Sciences, Clemson, SC 29634, USA.
  • Eccles-Miller JA; Clemson University, Biological Sciences, Clemson, SC 29634, USA.
  • Anderson E; Clemson University, Biological Sciences, Clemson, SC 29634, USA.
  • Farrell H; Clemson University, Biological Sciences, Clemson, SC 29634, USA.
  • Baldwin WS; Clemson University, Biological Sciences, Clemson, SC 29634, USA. Electronic address: baldwin@clemson.edu.
Prostaglandins Leukot Essent Fatty Acids ; 202: 102635, 2024 Aug 13.
Article em En | MEDLINE | ID: mdl-39142221
ABSTRACT
Non-Alcoholic Fatty Liver Disease (NAFLD) prevalence is rising and can lead to detrimental health outcomes such as Non-Alcoholic Steatohepatitis (NASH), cirrhosis, and cancer. Recent studies have indicated that Cytochrome P450 2B6 (CYP2B6) is an anti-obesity CYP in humans and mice. Cyp2b-null mice are diet-induced obese, and human CYP2B6-transgenic (hCYP2B6-Tg) mice reverse the obesity or diabetes progression, but with increased liver triglyceride accumulation in association with an increase of several oxylipins. Notably, 9-hydroxyoctadecadienoic acid (9-HODE) produced from linoleic acid (LA, 182, ω-6) is the most prominent of these and 9-hydroxyoctadecatrienoic acid (9-HOTrE) from alpha-linolenic acid (ALA, 183, ω-3) is the most preferentially produced when controlling for substrate concentrations in vitro. Transactivation assays indicate that 9-HODE and 9-HOTrE activate PPARα and PPARγ. In Seahorse assays performed in HepG2 cells, 9-HOTrE increased spare respiratory capacity, slightly decreased palmitate metabolism, and increased non-glycolytic acidification in a manner consistent with slightly increased glutamine utilization; however, 9-HODE exhibited no effect on metabolism. Both compounds increased triglyceride and pyruvate concentrations, most strongly by 9-HOTrE, consistent with increased spare respiratory capacity. qPCR analysis revealed several perturbations in fatty acid uptake and metabolism gene expression. 9-HODE increased expression of CD36, FASN, PPARγ, and FoxA2 that are involved in lipid uptake and production. 9-HOTrE decreased ANGPTL4 expression and increased FASN expression consistent with increased fatty acid uptake, fatty acid production, and AMPK activation. Our findings support the hypothesis that 9-HODE and 9-HOTrE promote steatosis, but through different mechanisms as 9-HODE is directly involved in fatty acid uptake and synthesis; 9-HOTrE weakly inhibits mitochondrial fatty acid metabolism while increasing glutamine use.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Prostaglandins Leukot Essent Fatty Acids Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Prostaglandins Leukot Essent Fatty Acids Ano de publicação: 2024 Tipo de documento: Article