Decreasing Phosphatidylcholine on the Surface of the Lipid Droplet Correlates with Altered Protein Binding and Steatosis

Abstract

Alcoholic fatty liver disease (AFLD) is characterized by an abnormal accumulation of lipid droplets (LDs) in the liver. Here, we explore the composition of hepatic LDs in a rat model of AFLD. Five to seven weeks of alcohol consumption led to significant increases in hepatic triglyceride mass, along with increases in LD number and size. Additionally, hepatic LDs from rats with early alcoholic liver injury show a decreased ratio of surface phosphatidylcholine (PC) to phosphatidylethanolamine (PE). This occurred in parallel with an increase in the LD association of perilipin 2, a prominent LD protein. To determine if changes to the LD phospholipid composition contributed to differences in protein association with LDs, we constructed liposomes that modeled the LD PC:PE ratios in AFLD and control rats. Reducing the ratio of PC to PE increased the binding of perilipin 2 to liposomes in an in vitro experiment. Moreover, we decreased the ratio of LD PC:PE in NIH 3T3 and AML12 cells by culturing these cells in choline-deficient media. We again detected increased association of specific LD proteins, including perilipin 2. Taken together, our experiments suggest an important link between LD phospholipids, protein composition, and lipid accumulation.

Role of Elevated Intracellular S-Adenosylhomocysteine in the Pathogenesis of Alcohol-Related Liver Disease

“…DZA’s effects occurred largely by (1) increasing TG biosynthesis, (2) decreasing TG lipolysis, and (3) enhancing LD fusion events, thereby expanding the volume of existing LDs. We previously reported that alcohol-induced increases in liver TG and the accumulation of LDs are associated with methylation defects caused by higher levels of intracellular SAH and a lower SAM:SAH ratio [ 1 , 2 , 12 , 13 , 14 ]. We have also shown that treatment with betaine, which blocks the ethanol-induced rise in intracellular SAH and normalizes the reduced SAM:SAH ratio, prevents steatosis and LD accumulation [ 1 , 12 , 13 , 14 ].…”

“…The earliest manifestation of alcohol-induced liver injury is steatosis, characterized by fat accumulation in this organ, which, histologically, is seen as higher numbers and larger sizes of specialized organelles called lipid droplets (LDs) in the cytoplasm of the hepatocyte [ 1 , 2 ]. LDs are the main storage depots for intracellular lipids [ 3 ].…”

“…Recently, we discovered that many hallmark features of alcoholic liver injury, including accumulation of larger-sized LDs, correlated with a reduced ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) associated with higher intracellular SAH levels [ 1 , 2 , 12 , 13 , 14 ]. We further reported that the rise in LD size correlated inversely with its surface PC to PE content and that a reduction in the PC:PE ratio caused increased recruitment of PLINs [ 1 ], which are negative regulators of LD TG hydrolysis [ 15 , 16 ].…”

“…We further reported that the rise in LD size correlated inversely with its surface PC to PE content and that a reduction in the PC:PE ratio caused increased recruitment of PLINs [ 1 ], which are negative regulators of LD TG hydrolysis [ 15 , 16 ]. More importantly, strategies designed to prevent SAH elevation, such as betaine administration to ethanol-fed animals, also prevent alcohol-induced LD accumulation [ 1 , 2 , 12 , 13 , 14 ]. Based on these findings, we hypothesized that increases in intracellular SAH alone would result in lipid accumulation similar to that seen after alcohol exposure.…”

Playing Jekyll and Hyde—The Dual Role of Lipids in Fatty Liver Disease

“…Interestingly, lipid analysis in these mice revealed that phosphatidylethanolamine (PE) to phosphatidylcholine (PC) conversion mediated by the enzyme phosphatidylethanolamine N-methyltransferase (PEMT) was affected [ 71 ]. Higher PE/PC ratios on LDs are associated with liver injury in rats [ 73 ]. More recently, the specific role of Plin2 in hepatocytes was studied in more detail by comparing full-body and liver-specific Plin2 deletion.…”