Htd2 deficiency-associated suppression of α-lipoic acid production provokes mitochondrial dysfunction and insulin resistance in adipocytes

Abstract

Mitochondria harbor a unique fatty acid synthesis pathway (mtFAS) with mysterious functions gaining increasing interest, while its involvement in metabolic regulation is essentially unknown. Here we show that 3-Hydroxyacyl-ACP dehydratase (HTD2), a key enzyme in mtFAS pathway was primarily downregulated in adipocytes of mice under metabolic disorders, accompanied by decreased de novo production of lipoic acid, which is the byproduct of mtFAS pathway. Knockdown of Htd2 in 3T3-L1 preadipocytes or differentiated 3T3-L1 mature adipocytes impaired mitochondrial function via suppression of complex I activity, resulting in enhanced oxidative stress and impaired insulin sensitivity, which were all attenuated by supplement of lipoic acid. Moreover, lipidomic study revealed limited lipid alterations in mtFAS deficient cells which primarily presenting accumulation of triglycerides, attributed to mitochondrial dysfunction. Collectively, the present study highlighted the pivotal role of mtFAS pathway in regulating mitochondrial function and adipocytes insulin sensitivity, demonstrating supportive evidence for lipoic acid being potential effective nutrient for improving insulin resistance and related metabolic disorders.

α-Lipoic Acid Alleviates Hepatic Lipid Deposition by Inhibiting FASN Expression via miR-3548 in Rats

“…Another report showed that α-lipoic acid supplementation suppresses de novo lipogenesis by reducing FASN and SCD1 in mice [ 30 , 31 ]. Recent results support α-lipoic acid as an effective mitochondrial nutrient to improve insulin resistance in Htd2 knockdown adipocytes [ 46 ]. Furthermore, FABP1-ablated mice show reduced hepatic TGs through modulation of murine stellate cell activation or disruption of net fatty acid uptake and utilization [ 47 , 48 ].…”

The effect of alpha-lipoic acid supplementation on anthropometric, glycemic, lipid, oxidative stress, and hormonal parameters in individuals with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials

“…However, it is crucial to acknowledge that the influence of ALA extends beyond skeletal muscles, as it inhibits gluconeogenesis and glucose production in the liver [ 42 , 43 ]. Furthermore, ALA exerts a partially positive impact on insulin metabolic pathways [ 44 ]. Numerous studies have indicated that ALA boosts the efficiency of distinct proteins involved in the insulin signaling pathway, such as insulin receptor, phosphatidylinositide 3-kinase [ 45 ], insulin receptor substrate 1 [ 46 , 47 ], and protein kinase B [ 48 ].…”

The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism

“…However, it is possible it is required because mitochondria are hubs for sulphur homeostasis and the mtFAS-mediated biosynthesis of lipoate requires sulphur from Fe–S clusters [ 52 , 53 ]. Furthermore, several studies that knocked out genes encoding the components of mtFAS identified mitochondrial lipogenesis is vital for bioenergetics and tissue function [ 54 , 55 ]. This has also sparked discussions surrounding the role of defective mtFAS in the manifestation of metabolic diseases like metabolic dysfunction-associated fatty liver disease (MAFLD), obesity, and type 2 diabetes mellitus (T2DM).…”