Role of intramyocelluar lipids in human health

Abstract

Intramyocellular lipid (IMCL) is predominantly stored as intramuscular triglyceride (IMTG) in lipid droplets and is utilized as metabolic fuel during physical exercise. IMTG is also implicated in muscle insulin resistance (IR) in type 2 diabetes. However, it has become apparent that lipid moieties such as ceramide and diacylglycerol are the likely culprits of IR. This article reviews current knowledge of IMCL-mediated IR and important areas of investigation, including myocellular lipid transport and lipid droplet proteins. Several crucial questions remain unanswered, such as the identity of specific ceramide and diacylglycerol species that mediate IR in human muscle and their subcellular location. Quantitative lipidomics and proteomics of targeted subcellular organelles will help to better define the mechanisms underlying pathological IMCL accumulation and IR.

Figure 1

Role of intramyocelluar lipid (IMCL) during exercise and in obesity. This schematic depicts the fate of the major IMCL lipid species within the context of exercise and obesity. During exercise, fatty acid (FA) acyl CoA is oxidized by mitochondria to synthesize ATP. FA acyl CoA is also partitioned to lipid droplets (LDs), where it is esterified to triglyceride (TG). TG can subsequently be lyophilized to release FAs for mitochondrial oxidation. In obesity, because of lower energetic demand, most FA acyl CoA is partitioned to LDs. IMCL in LDs can then act as a surrogate for ceramide and DAG. FA CoA oversupply to mitochondria during low energetic demand results in incomplete β oxidation and reactive oxygen species (ROS) production. The size of the arrows represents the rate of flux. Ab, albumin.

Figure 2

Putative role of saturated and unsaturated fatty acids (FAs) in mediating insulin resistance (IR). In obesity, saturated FAs may result in preferential accumulation of ceramide, which mediates IR by inhibiting phosphorylation and activation of protein kinase B (PKB). Conversely, unsaturated FAs may preferentially result in diacylglycerol accumulation and subsequent activation of protein kinase C theta (PKCθ), leading to serine phosphorylation of insulin receptor substrate-1 (IRS-1) and IR.