Transcriptional regulation of lipogenesis and its contribution to hepatosteatosis

Abstract

are tightly and coordinately regulated, including enzymes in FA synthesis, such as ACL, ACC, FAS and stearoyl-CoA desaturase, enzymes in the production of NADPH required for FAS activity, such as malic enzyme and glucose-6-phosphate dehydrogenase, as well as enzymes in esterification for TAG synthesis, such as mGPAT and diacylglycerol acyltransferase. Some glycolytic enzymes, such as glucokinase and liver pyruvate kinase, are also regulated in a similar fashion to lipogenic enzymes to provide the carbon source for FA and TAG synthesis. The principal mode of long-term coordinated regulation of lipogenic gene expression in the liver is at the transcriptional level. The expression of the various enzymes mentioned above is very low in the fasted state, correlating with an increase in circulating glucagon, which raises cAMP levels in the liver to activate PKA for suppression of lipogenic gene transcription [2]. By contrast, in the fed state, especially after a high carbohydrate meal, both high blood glucose and insulin levels contribute to the drastic transcriptional activation of lipogenic genes. ChREBP, an E-box binding bHLH/LZ transcription factor that heterodimerizes with Mlx binds to the carbohydrateresponse element (ChoRE) present in lipogenic genes and confers glucose-mediated activation in the liver [3]. ChREBP is phosphorylated by PKA to decrease its nuclear localization, preventing glucose-induced transcriptional activation, whereas dephosphorylation of ChREBP by PP2A leads to activation [4]. Xylulose-5-phosphate produced in the pentose phosphate shunt has been proposed to signal the glucose effect [5]. However, a recent report suggests that glucose-6-phosphate Nonalcoholic fatty liver disease & lipogenesis Nonalcoholic fatty liver disease is the most common chronic liver disease encompassing a range from simple fatty liver (hepatosteatosis) to nonalcoholic steatohepatitis, which can further progress into fibrosis and cirrhosis. Nonalcoholic fatty liver disease is intimately associated with the metabolic syndrome and Type 2 diabetes and may, in effect, be a hepatic manifestation of the metabolic syndrome. Conversely, obesity, dyslipidemia and insulin resistance may also contribute to the development of nonalcoholic fatty liver disease. Hepatosteatosis, or excess accumulation of triglycerides (TAGs) in the liver, may arise due to an impairment of the normal processes of fatty acid (FA) and TAG metabolism (i.e., by increased synthesis of FAs and TAGs, or by decreased hydrolysis of TAG [lipolysis]) and FA oxidation in the liver. Decreased secretion of TAGs into circulation in the form of VLDL can also affect hepatic TAG levels. TAGs in the liver are formed by esterification of glycerol-3-phosphate with FAs. The FAs used for TAG synthesis can be those taken up from lipoproteins or free FAs released from adipose tissue in the circulation, as well as FAs synthesized de novo in the liver from excess dietary carbohydrates. In this article, we focus on the contribution of FA and TAG synthesis to the development of hepatosteatosis.