Acetylation of malate dehydrogenase 1 promotes adipogenic differentiation via activating its enzymatic activity

Abstract

This article is available online at http://www.jlr.org deacetylases (HDACs) and histone acetyltransferases are enzymes that catalyze deacetylation and acetylation of the -amino groups of lysine residues of proteins. Lysine acetylation was fi rst discovered to occur in histones, and histone acetylation is important in controlling the structure and function of chromatin ( 1 ). A large number of studies have further shown the existence of acetylated nonhistone proteins, including transcription factors, hormone receptors, signal transducers, and chaperones. The reversible acetylation of nonhistone proteins modulates a wide variety of key cellular processes, such as apoptosis, survival, and proliferation. Recently, several groups have reported that many metabolic enzymes are highly acetylated ( 2-5 ). Such enzymes are involved in glycolysis, fatty acid metabolism, gluconeogenesis, the TCA cycle, and the urea cycle, and the acetylation of these proteins regulates their activity so that they can respond to the metabolic demands of cells.Adipose tissue, which consists of loose connective tissue composed of adipocytes, is an important metabolic organ that functions in energy homeostasis ( 6 ). Adipocytes regulate physiologic processes, including glucose metabolism, angiogenesis, the infl ammatory response, and reproductive functions through secreted adipokines. Adipocyte differentiation can contribute to the development of obesity via a positive energy balance (energy intake > energy expenditure) ( 7 ). Obesity leads to serious health problems all over the world. The coexistence of obesity, type II diabetes, dyslipidemia, and hypertension, known as metabolic syndrome, constitutes an increased risk for the development of cardiovascular diseases ( 8 ). In adipocytes, fatty acids are stored as triglycerides, which serve as the fuel for maintaining energy balance. Acetyl-CoA is the direct precursor in the synthesis of fatty acids, and all fatty acid carbons come from the acetyl group of acetyl-CoA. In addition, it has Abstract Acetylation is one of the most crucial posttranslational modifi cations that affect protein function. Protein lysine acetylation is catalyzed by acetyltransferases, and acetyl-CoA functions as the source of the acetyl group. Additionally, acetyl-CoA plays critical roles in maintaining the balance between carbohydrate metabolism and fatty acid synthesis. Here, we sought to determine whether lysine acetylation is an important process for adipocyte differentiation. Based on an analysis of the acetylome during adipogenesis, various proteins displaying signifi cant quantitative changes were identifi ed by LC-MS/MS. Of these identifi ed proteins, we focused on malate dehydrogenase 1 (MDH1). The acetylation level of MDH1 was increased up to 6-fold at the late stage of adipogenesis. Moreover, overexpression of MDH1 in 3T3-L1 preadipocytes induced a signifi cant increase in the number of cells undergoing adipogenesis. The introduction of mutations to putative lysine acetylation sites showed a signifi cant loss ...

Acetylome Analysis Reveals Diverse Functions of Lysine Acetylation in Mycobacterium tuberculosis

“…Therefore, lysine acetylation may regulate the central metabolic pathways at multiple sites in M. tuberculosis. Among the enzymes shown to be acetylated in the central metabolic pathways, eight are components of the citrate cycle (12,55,56) and two enzymes, isocitrate lyase (ICL-1) and malate synthase G (GlcB), are involved in the glyoxylate pathway. In M. tuberculosis, both copies of the isocitrate-lyase-encoding genes are required for the survival of the bacterium in vivo (57,58).…”

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“…104 Malate dehydrogenase 1 (MDH1) is involved in gluconeogenesis. 106 Indeed, these genes can be targeted to manipulate the differentiation of ESCs into specific cardiomyocyte phenotypes or to modulate the maturation grade of cardiomyocytes derived from ESCs. In this context, it has been demonstrated that immature cardiomyocytes from fetal heart metabolize lactate to produce pyruvate to drive OXPHOS for ATP generation.…”

“…Protein phosphatase 1, regulatory subunit 3C (PPP1R3C), phosphorylase, glycogen, muscle (PYGM), enolase 3 (β, muscle; ENO3), phosphoglycerate mutase 2 (muscle; PGAM2), and amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL) regulate the degradation of glycogen into glucose (glycogenolysis). 99,[101][102][103][104][105][106][107][108] Phosphofructokinase, muscle (PFKM) catalyzes the phosphorylation of fructose-6-phosphate during glycolysis. 104 Malate dehydrogenase 1 (MDH1) is involved in gluconeogenesis.…”

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“…MDH1 catalyzes reversible oxidation of malate to oxaloacetate and plays an important role in transporting NADH equivalents across the mitochondrial membrane [67]. A recent study demonstrated that acetylation of MDH1 is elevated in 3T3-L1 preadipocytes and promotes adipogenic differentiation [68], thereby providing evidence that adipogenic differentiation is regulated by acetylation of MDH1. MDH1 acetylation is a cross-talk mechanism between adipogenesis and the intracellular energy level [68].…”