Structure, Function and Metabolism of Hepatic and Adipose Tissue Lipid Droplets: Implications in Alcoholic Liver Disease

Abstract

For more than 30 years, lipid droplets (LDs) were considered as an inert bag of lipid for storage of energy-rich fat molecules. Following a paradigm shift almost a decade ago, LDs are presently considered an active subcellular organelle especially designed for assembling, storing and subsequently supplying lipids for generating energy and membrane synthesis (and in the case of hepatocytes for VLDL secretion). LDs also play a central role in many other cellular functions such as viral assembly and protein degradation. Here, we have explored the structural and functional changes that occur in hepatic and adipose tissue LDs following chronic ethanol consumption in relation to their role in the pathogenesis of alcoholic liver injury.

Keywords: ATGL; HCV; HSL; Liver; MiRs; Src; TGH; VLDL; adipose; alcohol; betaine; dynamin; lipases; lipid; lipid droplet; lipolysis; lipophagy; perilipin; phosphatidylcholine; phosphatidylethanolamine; rab; steatosis; triglycerides.

Figure 1. Diagrammatic Structure of Lipid Droplets

Lipid droplets (LDs) are composed of a homogenous lipid core covered by a monolayer coating of phospholipids, free cholesterol and lysophospholipids. The hydrophobic core of LDs is made of neutral lipids with tri- and diacylglycerols, esterified cholesterol and retinyl esters. The surface of LDs is also studded with several different proteins including perilipins and RabGTPase’s.

Figure 2. Diverse functions of Liver Lipid droplets

Lipid droplet (LD) is an active subcellular organelle that performs many cellular functions in the liver as shown.

Figure 3. Schematic representation of many players that regulate lipid droplet formation and degradation

The protein and lipid factors within lipid droplets (LDs) must be maintained in a delicate balance for effective lipolysis. Any change in the structure or interactions of these components can alter lipid droplet formation and their degradation. Hepatic phosphatidylethanolamine methyltransferase (PEMT) maintains phospholipids composition of the LD for normal lipolysis to facilitate VLDL production and secretion to ultimately prevent LD accumulation. In addition, lipases, active RabGTPases such as Rab7 and dynamin 2 activate lipolysis/vesiculation and prevent LD accumulation. LD also recruits core autophagic machinery and LAMP-2A dependent chaperone-mediated autophagy of Perilipin2 (Plin2) thereby favoring lipolysis. Several microRNAs (miRs) listed reportedly prevent LD accumulation. Alternatively, several other miRs, Plin2 and HCV proteins all promote LD accumulation in the liver.

Figure 4. Major mechanisms by which ethanol promotes adipocyte LD lipolysis

Ethanol induces LD lipolysis in white adipose tissue (WAT) loss through activation of the lipases (HSL and ATGL). Insulin resistance that develops with chronic ethanol abuse promotes WAT LD lipolysis via ATGL activation. Further ethanol-induced oxidative stress also induces ATGL expression in a FoxO1-dependent manner. Ethanol-induced changes in adipose S-adenosylmethionine:S-adenosylhomocysteine (SAM:SAH) ratio enhance HSL activation to promote LD lipolysis. Betaine can prevent activation of the lipases via normalizing adipose SAM:SAH ratios and preventing homocystenemia.

Figure 5. Multiple mechanisms by which ethanol facilitates lipid droplet accumulation in the liver

In the healthy liver, the number and size of lipid droplets (LDs) are tightly regulated and there is an orchestrated re-distribution of stored triglycerides (TAG) following lipolysis. Ethanol-induced changes in LD phospholipid and protein composition inhibits LD lipolysis, TAG turnover and VLDL secretion causing LD accumulation in the liver. Betaine via its ability to normalize hepatocellular methylation potential (S-adenosylmethionine:S-adenosylhomocysteine [SAM:SAH] ratio) could normalize LD phospholipid composition to promote lipolysis and VLDL secretion, thereby preventing LD accumulation.