Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective
Introduction
Triacylglycerol (TAG) is synthesized by esterification of glycerol-3-phosphate with fatty acids (FA) taken up from the diet as well as with FA synthesized de novo (de novo lipogenesis) from excess dietary carbohydrates (Figure 1). The two major tissues that synthesize FA and TAG at a high level in adults are the so-called lipogenic tissues, liver and adipose tissue. TAG synthesized in the liver is used for VLDL assembly to be secreted to the circulation so that various tissues take up FA from VLDL-TAG upon hydrolysis. TAG synthesized in adipose tissue, on the other hand, is stored as the main energy storage form in mammals, and is hydrolyzed in adipose tissue to release FA into the circulation to be used by other tissues during periods of energy demand.
Dysregulation of FA and TAG metabolism often contributes to metabolic diseases. Excess synthesis and storage of TAG in adipose tissue due to caloric intake above the expenditure, that is, obesity, is a global health epidemic in modern times and is strongly associated with insulin resistance, liver steatosis, dyslipidemia, and cardiovascular diseases [1, 2•]. Paradoxically, the metabolic abnormalities usually found in obesity are also associated with lipodystrophy which is characterized by selective loss of adipose tissue mass from particular regions of the body. Although the underlying molecular mechanisms are not clear, in lipodystrophic patients, metabolic complications may result from ectopic storage of TAG in tissues such as liver and muscle. Furthermore, in cancer cells, aerobic glycolysis, instead of oxidative phosphorylation, provides energy (so-called Warburg effect) [3]. Increased glycolysis facilitates an increase in de novo lipogenesis, providing FA for membrane phospholipid biosynthesis in cancer cells. Thus, lipogenic enzymes not only are used as markers for certain types of human cancers, but also are being exploited as potential anti-cancer targets [4]. In light of the implications of this wide range of health problems, it is critical to understand the regulation of fatty acid and TAG synthesis. While this review provides a brief review of the transcriptional regulation of lipogenic genes during fasting/feeding, it focuses mainly on the recent development of the role of USF, SREBP-1c, and LXRα on transcriptional activation of lipogenic genes by insulin.
Section snippets
Regulation of fatty acid and triacylglycerol synthesis
FA and TAG synthesis in lipogenic tissues is under nutritional and hormonal control. Many of the enzymes involved in FA and TAG synthesis are tightly and coordinately regulated during fasting/feeding. The coordinately regulated enzymes include: enzymes in the FA synthetic pathway, such as ATP-citrate lyase (ACL), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS); enzymes involved in the production of NADPH required for FAS activity, such as malic enzyme and enzymes in hexose
USF
In the earliest studies of insulin regulation of the FAS promoter, our laboratory showed that binding of the bHLH-LZ transcription factors, upstream-stimulatory factor-1 and upstream-stimulatory factor-2 (USF-1/USF-2) heterodimer, to the −65 E-box is required for transcriptional activation by insulin in 3T3-L1 adipocytes [6, 7, 8] (Figure 3a). Overexpression of dominant negative USF impaired FAS promoter activation. Furthermore, functional analysis and chromatin immunoprecipitation (ChIP) in
SREBP-1c
Sterol-regulatory element binding protein (SREBP), another bHLH-LZ transcription factor, was originally identified as a transcription factor that binds to SRE for cholesterol regulation [18]. SREBP is present in the endoplasmic reticulum membrane as a transmembrane protein precursor. Nuclear entry of SREBP requires proteolytic cleavage of the cytoplasmic N-terminal domain. Of the three members of the SREBP family, SREBP-1a, SREBP-1c and SREBP-2, SREBP-1c is highly expressed in lipogenic tissue,
LXR
Liver X receptor (LXR) is a ligand-activated transcription factor that belongs to nuclear receptor superfamily. Of the two LXR isoforms, LXRα is abundantly expressed in lipogenic tissues and, by activating the SREBP-1c promoter, it plays an important role in the transcriptional activation of lipogenic genes. Thus, in LXRα knockout as well as LXRα/β double knockout mice, SREBP-1c and FAS levels were lower resulting in a decrease in hepatic and plasma TAG levels. Furthermore, LXR agonists such as
Conclusion
FA and TAG synthesis is a highly regulated cellular process crucial to the metabolic homeostasis of organisms. Dysregulation of lipid metabolism can often lead to adverse consequences such as obesity, hepatic steatosis, diabetes and cardiovascular diseases. Therefore, it is crucial to dissect the process of FA and TAG synthesis. Transcription of lipogenic enzymes is highly regulated by insulin and glucose. For insulin-mediated regulation, the major transcription factors involved are USF,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The work from authors’ laboratory is supported by NIH grants, DK081098 and DK075682, to H. S. S. We thank members of Sul laboratory for critical reading of the manuscript.
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