Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases

Abstract

Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential for maintaining physiological functions and metabolic homeostasis. However, chronic elevation of BCAAs causes metabolic diseases such as obesity, type 2 diabetes (T2D), and metabolic-associated fatty liver disease (MAFLD). Adipose tissue, skeletal muscle, and the liver are the three major metabolic tissues not only responsible for controlling glucose, lipid, and energy balance but also for maintaining BCAA homeostasis. Under obese and diabetic conditions, different pathogenic factors like pro-inflammatory cytokines, lipotoxicity, and reduction of adiponectin and peroxisome proliferator-activated receptors γ (PPARγ) disrupt BCAA metabolism, leading to excessive accumulation of BCAAs and their downstream metabolites in metabolic tissues and circulation. Mechanistically, BCAAs and/or their downstream metabolites, such as branched-chain ketoacids (BCKAs) and 3-hydroxyisobutyrate (3-HIB), impair insulin signaling, inhibit adipogenesis, induce inflammatory responses, and cause lipotoxicity in the metabolic tissues, resulting in multiple metabolic disorders. In this review, we summarize the latest studies on the metabolic regulation of BCAA homeostasis by the three major metabolic tissues-adipose tissue, skeletal muscle, and liver-and how dysregulated BCAA metabolism affects glucose, lipid, and energy balance in these active metabolic tissues. We also summarize therapeutic approaches to restore normal BCAA metabolism as a treatment for metabolic diseases.

Keywords: BCAAs; adipose tissue; diabetes and obesity; liver; metabolic tissues; skeletal muscle.

FIGURE 1

Overview of BCAA catabolism and crosstalk with different metabolic pathways. BCAAs are catabolized via multistep reactions. The rate‐limiting enzyme BCKDHA is positively and negatively regulated by PPM1K and BCKDK, respectively. BCAA‐derived acetyl‐ and succinyl‐CoA can enter the TCA cycle to generate ATP or anaplerosis. BCAAs can affect glucose oxidation by inhibiting the pyruvate dehydrogenase complex. The regulatory enzymes PPM1K and BCKDK also regulate the ATP citrate lyase (involved in lipogenesis) in the liver. Metabolites 3‐HIB can alter the fatty acid transport in the endothelial cells of skeletal muscle. Adapted from “Overview of BCAA Catabolic Enzymes”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender‐templates.

FIGURE 2

BCAA catabolism in adipose tissue under physiological and pathophysiological conditions. Under physiological conditions, BCAAs are as a substrate for adipogenesis (by activating mTORC1/S6K1 axis), lipogenesis (via the production of mmBCFA), and thermogenesis. While under pathological conditions, a higher level of BCAAs and their associated metabolites affects different processes in adipose tissue. Elevated BCKA levels suppress the WAT‐beiging by inhibiting the binding of PRDM16 to PPARγ, and promote macrophage polarization. The knockdown of BCKDHA impairs adipogenesis and thermogenesis. A reduced rate of BCAA catabolism is also linked with hypoxia and adipose tissue fibrosis. Additionally, the blockage of BCAA transporter SLC7A10 leads to higher production of 3‐HIB in adipocytes, and an inverse correlation has been observed in sWAT SLC7A10 expression and BCAA levels. Figure created with BioRender.com.

FIGURE 3

Role of BCAA catabolism in skeletal muscle under physiological and pathophysiological conditions. BCAAs induce protein synthesis and increase muscle fiber mass and size by activating the mTORC1 pathway and ATP production. However, chronic elevation of BCAAs/BCKAs leads to hyperactivation of mTORC1, and thus impairment of insulin signaling. BCKAs also suppress insulin‐mediated glucose uptake by inhibiting the phosphorylation of AKT. 3‐HIB causes lipotoxicity by increasing the transport of fatty acids. Defective OXPHOS can induce more production of acetyl‐CoA, which can lead to an increase in de novo lipogenesis and ROS production via blocking mitochondria complex II (succinate dehydrogenase A [SDHA]) in skeletal muscle. Figure created with BioRender.com.

FIGURE 4

BCAA catabolism in the liver under physiological and pathophysiological conditions. Apart from producing ATP, BCAAs generate the substrate for hepatic gluconeogenesis. The liver plays a crucial role in detoxifying the ammonia generated during BCAA catabolism. BCAAs induce the synthesis of liver proteins via mTORC1activation. On the other hand, elevated levels of BCAAs/BCKAs/3‐HIB induce fatty acid uptake, and steatosis, and impair insulin signaling. Figure created with BioRender.com.

FIGURE 5

Different pharmacological compounds targeting BCAA catabolic machinery. Different pharmacological compounds target BCKCK, PPM1K, and BCAT2 (as shown in the figure) to boost BCAA catabolism and produce beneficial effects against metabolic diseases. Figure created with BioRender.com.

FIGURE 6

Therapeutic interventions for promoting BCAA catabolism or reducing BCAA biosynthesis in metabolic diseases. Figure created with BioRender.com.