malonyl-coenzyme-a and Metabolic-Syndrome

The metabolic syndrome can be defined as a state of metabolic dysregulation characterized by insulin resistance, central obesity, and a predisposition to type 2 diabetes, dyslipidemia, premature atherosclerosis, and other diseases. An increasing body of evidence has linked the metabolic syndrome to abnormalities in lipid metabolism that ultimately lead to cellular dysfunction. We review here the hypothesis that, in many instances, the cause of these lipid abnormalities could be a dysregulation of the adenosine monophosphate-activated protein kinase (AMPK)/malonyl coenzyme A (CoA) fuel-sensing and signaling mechanism. Such dysregulation could be reflected by isolated increases in malonyl CoA or by concurrent changes in malonyl CoA and AMPK, both of which would alter intracellular fatty acid partitioning. The possibility is also raised that pharmacological agents and other factors that activate AMPK and/or decrease malonyl CoA could be therapeutic targets.

Topics: AMP-Activated Protein Kinases; Animals; Energy Metabolism; Humans; Insulin Resistance; Lipid Metabolism; Malonyl Coenzyme A; Metabolic Syndrome; Multienzyme Complexes; Protein Serine-Threonine Kinases; Signal Transduction

Topics: Adenylate Kinase; Animals; Fatty Acids; Humans; Malonyl Coenzyme A; Metabolic Syndrome; Signal Transduction

Metabolic syndrome is defined as a clustering of cardiovascular risk factors (abdominal obesity, hyperinsulinemia, atherogenic dyslipidemia, hypertension and hypercoagulability) that together increase the risk of developing coronary heart disease and type 2 diabetes. Inhibition of acetyl-CoA carboxylase (ACC), which results in inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect a multitude of cardiovascular risk factors associated with metabolic syndrome. ACC exists as two tissue-specific isozymes, ACC1 present in lipogenic tissues (liver and adipose) and ACC2 present in oxidative tissues (liver, heart and skeletal muscle). Studies in both ACC2 knockout mice and animals administered isozyme-nonselective ACC inhibitors have demonstrated the utility of treating metabolic syndrome through this modality. An isozyme-non-selective ACC inhibitor may potentially provide the optimal therapeutic for beneficially affecting metabolic syndrome. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition. While demonstrating clinical efficacy of an ACC inhibitor should be relatively straightforward, the heterogeneity of the patient population and the absence of established guidelines regarding approval endpoints for agents simultaneously affecting multiple aspects of metabolic syndrome will pose developmental challenges for initial market entries.

Topics: Acetyl-CoA Carboxylase; Animals; Enzyme Inhibitors; Fatty Acids; Humans; Isoenzymes; Malonyl Coenzyme A; Metabolic Syndrome

The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning.

Topics: Animals; Brain; Cardiovascular Diseases; Carnitine; Carnitine O-Palmitoyltransferase; Ceramides; Diabetes Mellitus, Type 2; Disease Progression; Eating; Endocannabinoids; Energy Metabolism; Fatty Acids; Humans; Hypoglycemia; Insulin; Learning; Lipid Metabolism, Inborn Errors; Malonyl Coenzyme A; Metabolic Syndrome; Mitochondria; Mitochondria, Liver; Mitochondria, Muscle; Multienzyme Complexes; Neurodegenerative Diseases; Oxidation-Reduction; Protein Isoforms