Plasma 3-hydroxyisobutyrate (3-HIB) and methylmalonic acid (MMA) are markers of hepatic mitochondrial fatty acid oxidation in male Wistar rats

Mona Synnøve Bjune,Carine Lindquist,Marit Hallvardsdotter Stafsnes,Bodil Bjørndal,Per Bruheim,Thomas A Aloysius,Ottar Nygård,Jon Skorve,Lise Madsen,Simon N Dankel,Rolf Kristian Berge

doi:10.1016/j.bbalip.2021.158887

Abstract

ObjectiveDiscovery of specific markers that reflect altered hepatic fatty acid oxidation could help to detect an individual's risk of fatty liver, type 2 diabetes and cardiovascular disease at an early stage. Lipid and protein metabolism are intimately linked, but our understanding of this crosstalk remains limited. MethodsIn male Wistar rats, we used synthetic fatty acid analogues (3-thia fatty acids) as a tool to induce hepatic fatty acid oxidation and mitochondrial biogenesis, to gain new insight into the link between fatty acid oxidation, amino acid metabolism and TCA cycle-related intermediate metabolites in liver and plasma. ResultsRats treated with 3-thia fatty acids had 3-fold higher hepatic, but not adipose and skeletal muscle, expression of the thioesterase 3-hydroxyisobutyryl-CoA hydrolase (Hibch), which controls the formation of 3-hydroxyisobutyrate (3-HIB) in the valine degradation pathway. Consequently, 3-thia fatty acid-stimulated hepatic fatty acid oxidation and ketogenesis was accompanied by decreased plasma 3-HIB and increased methylmalonic acid (MMA) concentrations further downstream in BCAA catabolism. The higher plasma MMA corresponded to higher MMA-CoA hydrolase activity and hepatic expression of GTP-specific succinyl-CoA synthase (Suclg2) and succinate dehydrogenase (Sdhb), and lower MMA-CoA mutase activity. Plasma 3-HIB correlated positively to plasma and hepatic concentrations of TAG, plasma total fatty acids, plasma NEFA and insulin/glucose ratio, while the reverse correlations were seen for MMA. ConclusionOur study provides new insight into TCA cycle-related metabolic changes associated with altered hepatic fatty acid flux, and identifies 3-HIB and MMA as novel circulating markers reflective of mitochondrial β-oxidation in male Wistar rats.

Highlights

Altered mitochondrial function in liver, adipose and muscle tissue has been suggested to underlie the development of insulin resistance and increased risk of developing several diseases [1,2,3,4]
We used mitochondria-targeted fatty acid analogues as tools to investigate branchedchain amino acid (BCAA) catabolism and cellular mechanisms related to TCA cycle activity, mitochondrial β-oxidation and lipid metabolism relevant in progression of metabolic diseases
As the fatty acid analogues used in this study primarily target the liver mitochondria, our results indicate that the circulating levels of 3-HIB and methyl malonic acid (MMA) may be controlled, at least in part, by the liver, which has high BCAA catabolic activity [10]

Summary

Introduction

Altered mitochondrial function in liver, adipose and muscle tissue has been suggested to underlie the development of insulin resistance and increased risk of developing several diseases [1,2,3,4]. In situations of excess hepatic lipid uptake, an adaptive increase in mitochondrial oxidative capacity can prevent fatty liver and related conditions including insulin resistance and type 2 diabetes [5]. We and others have recently reported altered levels of intermediary BCAA metabolites such as the valine-derived metabolite 3hydroxyisobutyrate (3-HIB) in obesity, insulin resistance and type 2 diabetes [16,17,18,19,20,21]. Another study found that 3HIB can promote insulin resistance in skeletal muscle by increasing endothelial fatty acid uptake [22]. The release of 3-HIB and other TCArelated dicarboxylic acids depends on the removal of Coenzyme A (CoA) groups via specific thioesterases, a type of hydrolases

Methods

Results

Conclusion