The development of fatty liver (steatosis) is an early manifestation of alcoholic liver disease (ALD) that can progress to alcoholic hepatitis and cirrhosis with continued alcohol misuse. Hepatic steatosis is a benign and reversible early stage of ALD. However, fat accumulation is regarded as the “first hit” that leaves the liver more vulnerable to multiple hits leading to ALD progression, and is therefore, a prime target for therapeutic intervention. Our long-term objective is to (i) understand the mechanisms of alcoholic steatosis development and (ii) formulate strategies for treatment/prevention of this and other fatty liver diseases that present with similar histopathological and disease progression characteristics such as non-alcoholic fatty liver disease. We have shown that alcohol-impaired activity of a major liver enzyme, phosphatidylethanolamine methyltransferase (PEMT), inhibits very-low-density lipoprotein (VLDL) secretion, contributing to the development of hepatic steatosis. PEMT catalyzes the methylation of phosphatidylethanolamine (PE) to generate phosphatidylcholine (PC), which is preferentially used in the assembly of VLDL and is necessary for its normal secretion. We have further shown that treatment with betaine, (a methyl donor) increases PC generation by normalizing PEMT activity. This, in turn, normalizes VLDL secretion rate and thus prevents alcoholic steatosis. It has been demonstrated that hepatic cytoplasmic lipid droplets (LDs) play an integral role in VLDL biogenesis. This is because VLDL assembly is regulated by the availability of triglycerides stored in these LDs which must be hydrolyzed to provide substrates for VLDL biogenesis. LDs are surrounded by a monolayer of phospholipids; PC is the most abundant class followed by PE. Further, an orbit of proteins determines the metabolic fate of LD lipid stores. Reduction in LD monolayer PC:PE ratio promotes fusion of these organelles to form supersized structures that are more resistant to lipolysis. Furthermore, a lower PC:PE ratio enhances the binding of the LD-associated proteins known to protect this organelle from lipase digestion. We have evidence that phospholipid and protein composition of hepatic LD changes with the initiation of alcohol-induced hepatic steatosis. Importantly, ethanol-induced hepatic LD accumulation occurs in conjunction with impaired VLDL production and enhanced adipose lipolysis-generated free fatty acid delivery and uptake. However, little is known about why alcohol promotes LD accumulation in hepatocytes but enhances adipocyte LD shrinkage. Based on these considerations, we present a novel hypothesis that alcohol impaired methylation contributes to the development of hepatic steatosis by inhibiting liver LD lipolysis and promoting adipose LD breakdown. We propose that liver phospholipid methylation defect lowers the LD monolayer PC:PE ratio to generate enlarged structures with altered composition of LD-associated proteins. These changes togeth...