The genetics of neutral lipid biosynthesis: an evolutionary perspective.

The storage of fatty acids and fatty alcohols in the form of neutral lipids such as triacylglycerol (TAG), cholesteryl ester (CE), and wax ester (WE) serves to provide reservoirs for membrane formation and maintenance, lipoprotein trafficking, lipid detoxification, evaporation barriers, and fuel in times of stress or nutrient deprivation. This ancient process likely originated in actinomycetes and has persisted in eukaryotes, albeit by different molecular mechanisms. A surfeit of neutral lipids is strongly, perhaps causally, related to several human diseases such as diabetes mellitus, obesity, atherosclerosis and nonalcoholic fatty liver disease. Therefore, understanding the metabolic pathways of neutral lipid synthesis and the roles of the enzymes involved may facilitate the development of new therapeutic interventions for these syndromes.

Nonalcoholic fatty liver disease: emerging mechanisms and consequences.

PURPOSE OF REVIEW: One of the critical complications of obesity and diabetes is nonalcoholic fatty liver disease, a disorder of triacylglycerol accumulation in the liver that has potential to develop into end stage liver failure. In this review, the recent progress in understanding the role of hepatic triacylglycerol synthesis in the development of nonalcoholic fatty liver disease is discussed. RECENT FINDINGS: It has become apparent that the development of hepatic steatosis is a complex, multifactorial process. Although the molecular pathways underlying its development have been described, there are no established therapies for nonalcoholic fatty liver disease. Recently, however, DGAT1 and DGAT2, the enzymes responsible for the final step in triacylglycerol synthesis, have been characterized as playing a vital role in hepatic triacylglycerol metabolism. Cellular and murine models in which diacylglycerol acyltransferase expression is altered suggest that these enzymes may play a role in the development hepatic steatosis, are feasible targets in the treatment of nonalcoholic fatty liver disease, but also function as lipotoxic buffers. SUMMARY: Hepatic steatosis remains the watershed event in the progression of nonalcoholic fatty liver disease. The diacylglycerol acyltransferases are emerging as important mediators of hepatic triacylglycerol accumulation. Therefore, these enzymes are attractive targets in the development of therapies to prevent liver triacylglycerol accumulation and the consequences of nonalcoholic fatty liver disease.

Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily.

The esterification of alcohols such as sterols, diacylglycerols, and monoacylglycerols with fatty acids represents the formation of both storage and cytoprotective molecules. Conversely, the overproduction of these molecules is associated with several disease pathologies, including atherosclerosis and obesity. The human acyl-CoA:diacylglycerol acyltransferase (DGAT) 2 gene superfamily comprises seven members, four of which have been previously implicated in the synthesis of di- or triacylglycerol. The remaining 3 members comprise an X-linked locus and have not been characterized. We describe here the expression of DGAT2 and the three X-linked genes in Saccharomyces cerevisiae strains virtually devoid of neutral lipids. All four gene products mediate the synthesis of triacylglycerol; however, two of the X-linked genes act as acyl-CoA wax alcohol acyltransferases (AWAT 1 and 2) that predominantly esterify long chain (wax) alcohols with acyl-CoA-derived fatty acids to produce wax esters. AWAT1 and AWAT2 have very distinct substrate preferences in terms of alcohol chain length and fatty acyl saturation. The enzymes are expressed in many human tissues but predominate in skin. In situ hybridizations demonstrate a differentiation-specific expression pattern within the human sebaceous gland for the two AWAT genes, consistent with a significant role in the composition of sebum.