Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway; Bevital AS, Bergen, Norway.
EBioMedicine. 2023 May;91:104569. doi: 10.1016/j.ebiom.2023.104569. Epub 2023 Apr 19.
The valine (branched-chain amino acid) metabolite 3-hydroxyisobutyrate (3-HIB), produced by 3-Hydroxyisobutyryl-CoA Hydrolase (HIBCH), is associated with insulin resistance and type 2 diabetes, but implicated tissues and cellular mechanisms are poorly understood. We hypothesized that HIBCH and 3-HIB regulate hepatic lipid accumulation.
HIBCH mRNA in human liver biopsies ("Liver cohort") and plasma 3-HIB ("CARBFUNC" cohort) were correlated with fatty liver and metabolic markers. Human Huh7 hepatocytes were supplemented with fatty acids (FAs) to induce lipid accumulation. Following HIBCH overexpression, siRNA knockdown, inhibition of PDK4 (a marker of FA β-oxidation) or 3-HIB supplementation, we performed RNA-seq, Western blotting, targeted metabolite analyses and functional assays.
We identify a regulatory feedback loop between the valine/3-HIB pathway and PDK4 that shapes hepatic FA metabolism and metabolic health and responds to 3-HIB treatment of hepatocytes. HIBCH overexpression increased 3-HIB release and FA uptake, while knockdown increased cellular respiration and decreased reactive oxygen species (ROS) associated with metabolic shifts via PDK4 upregulation. Treatment with PDK4 inhibitor lowered 3-HIB release and increased FA uptake, while increasing HIBCH mRNA. Implicating this regulatory loop in fatty liver, human cohorts show positive correlations of liver fat with hepatic HIBCH and PDK4 expression (Liver cohort) and plasma 3-HIB (CARBFUNC cohort). Hepatocyte 3-HIB supplementation lowered HIBCH expression and FA uptake and increased cellular respiration and ROS.
These data implicate the hepatic valine/3-HIB pathway in mechanisms of fatty liver, reflected in increased plasma 3-HIB concentrations, and present possible targets for therapeutic intervention.
Funding was provided by the Research Council of Norway (263124/F20), the University of Bergen, the Western Norway Health Authorities, Novo Nordisk Scandinavia AS, the Trond Mohn Foundation and the Norwegian Diabetes Association.
支链氨基酸（BCAA）代谢物 3-羟基异丁酸（3-HIB）由 3-羟基异丁酰辅酶 A 水解酶（HIBCH）产生，与胰岛素抵抗和 2 型糖尿病有关，但涉及的组织和细胞机制尚不清楚。我们假设 HIBCH 和 3-HIB 可调节肝脏脂质积累。
在人类肝活检（“Liver cohort”）和血浆 3-HIB（“CARBFUNC”队列）中，HIBCHmRNA 与脂肪肝和代谢标志物相关。用脂肪酸（FA）补充人 Huh7 肝细胞以诱导脂质积累。在过表达 HIBCH、siRNA 敲低、抑制 PDK4（FAβ氧化的标志物）或补充 3-HIB 后，我们进行了 RNA-seq、Western blot、靶向代谢物分析和功能测定。
我们鉴定了缬氨酸/3-HIB 途径与 PDK4 之间的调节反馈回路，该回路塑造了肝 FA 代谢和代谢健康，并对肝细胞的 3-HIB 治疗做出反应。HIBCH 过表达增加 3-HIB 释放和 FA 摄取，而敲低则增加细胞呼吸并降低与代谢变化相关的活性氧（ROS），通过上调 PDK4 实现。PDK4 抑制剂的处理降低了 3-HIB 的释放并增加了 FA 的摄取，同时增加了 HIBCH mRNA。该调节回路与脂肪肝有关，人类队列显示肝脂肪与肝 HIBCH 和 PDK4 表达（Liver cohort）和血浆 3-HIB（CARBFUNC cohort）呈正相关。肝细胞 3-HIB 补充降低了 HIBCH 表达和 FA 摄取，增加了细胞呼吸和 ROS。
这些数据表明，肝缬氨酸/3-HIB 途径参与了脂肪肝的发生机制，这反映在血浆 3-HIB 浓度的增加上，并为治疗干预提供了可能的靶点。
本研究由挪威研究理事会（263124/F20）、卑尔根大学、西挪威卫生当局、诺和诺德北欧公司、特隆赫姆莫恩基金会和挪威糖尿病协会提供资助。
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