9-HODE and 9-HOTrE alter mitochondrial metabolism, increase triglycerides, and perturb fatty acid uptake and synthesis associated gene expression in HepG2 cells

IF 3
William A Evans, Jazmine A Eccles-Miller, Eleanor Anderson, Hannah Farrell, William S Baldwin
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引用次数: 0

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, 18:2, ω-6) is the most prominent of these and 9-hydroxyoctadecatrienoic acid (9-HOTrE) from alpha-linolenic acid (ALA, 18:3, 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.

Abstract Image

9-HODE 和 9-HOTrE 会改变 HepG2 细胞的线粒体代谢,增加甘油三酯,扰乱脂肪酸摄取和合成相关基因的表达
非酒精性脂肪肝(NAFLD)的发病率正在上升,并可能导致非酒精性脂肪性肝炎(NASH)、肝硬化和癌症等有害健康的后果。最近的研究表明,细胞色素 P450 2B6 (CYP2B6) 在人类和小鼠体内是一种抗肥胖的 CYP。Cyp2b缺失的小鼠会因饮食诱发肥胖,而人类 CYP2B6 转基因(hCYP2B6-Tg)小鼠可逆转肥胖或糖尿病的发展,但肝脏甘油三酯积累增加,并伴有几种氧脂的增加。值得注意的是,由亚油酸(LA,18:2,ω-6)产生的 9-hydroxyoctadecadienoic acid(9-HODE)是其中最重要的一种,而在体外控制底物浓度时,由α-亚麻酸(ALA,18:3,ω-3)产生的 9-hydroxyoctadecatrienoic acid(9-HOTrE)是最优先产生的一种。反式激活试验表明,9-HODE 和 9-HOTrE 能激活 PPARα 和 PPARγ。在 HepG2 细胞中进行的海马试验中,9-HOTrE 增加了备用呼吸能力,略微降低了棕榈酸酯代谢,并以与略微增加谷氨酰胺利用率一致的方式增加了非糖酵解酸化;然而,9-HODE 对代谢没有影响。两种化合物都增加了甘油三酯和丙酮酸的浓度,其中 9-HOTrE 的影响最大,这与备用呼吸能力的增加一致。9-HODE 增加了参与脂质摄取和产生的 CD36、FASN、PPARγ 和 FoxA2 的表达。9-HOTrE 降低了 ANGPTL4 的表达,增加了 FASN 的表达,这与脂肪酸摄取、脂肪酸生成和 AMPK 激活的增加相一致。我们的研究结果支持这样的假设:9-HODE 和 9-HOTrE 促进脂肪变性,但通过不同的机制,因为 9-HODE 直接参与脂肪酸的摄取和合成;9-HOTrE 弱抑制线粒体脂肪酸代谢,同时增加谷氨酰胺的使用。
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来源期刊
Prostaglandins, leukotrienes, and essential fatty acids
Prostaglandins, leukotrienes, and essential fatty acids Clinical Biochemistry, Endocrinology, Diabetes and Metabolism
CiteScore
5.30
自引率
0.00%
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0
审稿时长
64 days
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