The role of lipid droplets in metabolic disease in rodents and humans

Abstract

Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease.

Figure 1. Alterations in LD proteins in adipocytes result in increased lipolysis and promote insulin resistance.

In lipoatrophic and obese humans, reduced expression of PLIN1, CIDEC, or CIDEA in adipocytes results in constitutive release of fatty acids (FA). These fatty acids act locally and enter the bloodstream, where they activate inflammatory pathways, promote ectopic lipid deposition in peripheral tissues, and cause insulin resistance. The released fatty acids act locally to promote insulin resistance and inflammation by: (a) engaging TLRs, resulting in activation of MAPK signaling pathways and release of inflammatory mediators, which block insulin actions on lipolysis and glucose uptake; (b) recruiting macrophages that amplify the inflammatory response; and (c) inducing ectopic lipid deposition in hepatocytes and skeletal muscle cells and activating inflammatory pathways. A reduction in PLIN1 increases constitutive lipolysis by allowing CGI-58, normally associated with PLIN1, to activate LD-associated and non-LD–associated ATGL. Reductions in CIDEA or CIDEC enhance lipolysis by unclear mechanisms. In humans, genetic alterations in seipin and caveolin-1 reduce adipose tissue mass, resulting in lipodystrophy.

Figure 2. Liver LD increases in obesity are linked to hepatic steatosis and insulin resistance.

Fatty acids from the diet or adipocyte lipolysis result in accumulation of neutral lipids in LD in hepatocytes and incorporation of PLIN2, PLIN3, CIDEA, CIDEB, CIDEC, and ATGL on the LD surface. In humans, PLIN1 is also found on hepatic LDs in individuals with NAFLD and NASH. Increased fatty acid accumulation and LD formation are in general associated with increased accumulation of diacylglycerol (DAG) and inflammatory cytokines. DAG activates atypical PKC, and fatty acids and cytokines activate inflammatory signaling pathways, which cumulatively block the actions of IRS-1 and -2 and promote insulin resistance. It is possible that DAG as well as TAG accumulate in LDs. In hepatocytes, insulin resistance is marked by increased hepatic gluconeogenesis and reduced glycogen formation. Notably, mutations in the phospholipase PNPLA3 result in hepatic steatosis.