Role of fatty acid elongase Elovl6 in the regulation of energy metabolism and pathophysiological significance in diabete
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REVIEW ARTICLE
Role of fatty acid elongase Elovl6 in the regulation of energy metabolism and pathophysiological significance in diabetes Takashi Matsuzaka1 Received: 18 November 2020 / Accepted: 30 November 2020 © The Japan Diabetes Society 2020
Abstract Type 2 diabetes mellitus (T2DM) is an expanding epidemic, closely linked to obesity. Peripheral insulin resistance and impaired insulin secretion remain the core defects in T2DM. Despite significant advances in unraveling the underlying these defects, many of the metabolic pathways and regulators involved in insulin resistance and β-cell dysfunction are not completely understood. This review proposes that manipulating the fatty acid (FA) composition by blocking ELOVL fatty acid elongase 6 (Elovl6) could protect against insulin resistance, impaired insulin secretion, and obesity-related disorders. The molecular mechanism of this new paradigm is also discussed. Elovl6 is a microsomal enzyme involved in the elongation of C16 saturated and monounsaturated FAs to form C18 FAs. We have reported that mice with Elovl6 deletion are protected against obesity-induced insulin resistance or β-cell failure when mated to leptin receptor-deficient db/db mice because the cellular FA composition is changed, even with concurrent obesity. Therefore, Elovl6 appears to be a crucial metabolic checkpoint, and limiting Elovl6 expression or activity could be a new therapeutic approach to treat T2DM. Keywords Obesity · Type 2 diabetes · Fatty acid · Elovl6 · Lipotoxicity
Introduction The increasing prevalence of obesity worldwide has become an alarming public health concern because of the associated rise in cases of obesity-associated diseases, including type 2 diabetes mellitus (T2DM) [1, 2]. Genetic and environmental factors contribute to the pathogenesis of T2DM, characterized by peripheral insulin resistance and insufficient compensation of insulin secretion by the pancreatic β-cells [3]. The accumulation of lipids, a phenomenon known as lipotoxicity, is a molecular link between obesity and glucose homeostasis dysregulation [4–6]. Most cellular lipid molecules include, as a major constituent, at least one fatty acid (FA). Most cells can synthesize FAs and the cellular FAs are diverse in carbon chain length and pattern of saturation/desaturation, which contributes to the variety of functions exhibited by the lipids [7]. Proper * Takashi Matsuzaka t‑[email protected] 1
Department of Endocrinology and Metabolism, Transborder Medical Research Centser, Faculty of Medicine, University of Tsukuba, 1‑1‑1 Tennodai, Tsukuba, Ibaraki 305‑8575, Japan
elongation and desaturation of FAs are essential for the maintenance of lipid homeostasis and disruption of these processes can have devastating consequences. ELOVL fatty acid elongase 6 (Elovl6) is an endoplasmic reticulum enzyme that catalyzes the chain elongation of C12–16 saturated and monounsaturated FAs to form C18 FAs, such as stearate (C18:0), oleate (C18:1n-9), and vaccinate (C18:1n-7) (Fig. 1) [8, 9]. These long chain FAs with
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