Sterol regulation of acetyl coenzyme A carboxylase: a mechanism for coordinate control of cellular lipid.

Abstract

Transcription from the housekeeping promoter for the acetyl coenzyme A carboxylase (ACC) gene, which encodes the rate-controlling enzyme of fatty acid biosynthesis, is shown to be regulated by cellular sterol levels through novel binding sites for the sterol-sensitive sterol regulatory element binding protein (SREBP)-1 transcription factor. The position ofthe SREBP sites relative to those for the ubiquitous auxiliary transcription factor Spl is reminiscent of that previously described for the sterol-regulated low density lipoprotein receptor promoter. The experiments provide molecular evidence that the metabolism of fatty acids and cholesterol, two different classes of essential cellular lipids, are coordinately regulated by cellular lipid levels.Fatty acids and cholesterol are both major constituents of animal cell membranes and their cellular levels must rise and fall together to provide a balanced supply for membrane biosynthesis and turnover during normal cellular growth. In addition, the liver plays a special role in lipid homeostasis since cholesterol and fatty acids are packaged into very low density lipoprotein (VLDL) particles that deliver their lipid to other sites in the body to maintain fat homeostasis (1). It is likely that there is a feedback mechanism to modulate the accumulation of both cholesterol and fatty acids for optimal cell growth and VLDL assembly.Coordinate regulation could be accomplished at least in part through the AMP-dependent protein kinase, which phosphorylates and inactivates both 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and acetyl coenzyme A carboxylase (ACC), the rate-controlling enzymes of cholesterol and fatty acid biosynthesis, respectively (2). While it is clear that a high ratio of AMP to ATP stimulates the kinase, other metabolic factors that modulate its activity are not well understood. Therefore, a role for the kinase in coordinating regulation in response to cellular lipid levels is unclear.Transcriptional control of genes that encode important enzymes of both cholesterol and fatty acid metabolism would be an alternative level for coordinate regulation to occur, and recent work has identified a family of activator proteins that could link the two pathways together. These sterol regulatory element binding proteins (SREBPs) activate transcription of the low density lipoprotein (LDL) receptor and HMG CoA synthase genes, which are essential for cholesterol uptake and biosynthesis, respectively (3, 4). cDNAs for SREBP-1 and -2 were cloned with specific oligonucleotide probes predicted by the amino acid sequence of the purified polypeptides (3, 4). Both SREBP proteins bind the same cis-acting elements in the LDL receptor and HMG CoA synthase promoters and activate expression only when cellular sterol levels fall below that required for optimal cell function (5).Independently, SREBP-1 was cloned from an adipocyte cDNA expression library with a DNA recognition site probe containing a special "E-box" sequence (6). Its mRNA wasThe publication costs of t...

Dietary acetic acid reduces serum cholesterol and triacylglycerols in rats fed a cholesterol-rich diet

“…HMG-CoA synthesis is catalysed by HMG-CoA synthase. While the transcription of this enzyme is regulated by SREBP-1a or -2 (Horton et al 1998), it has been reported that cholesterol reduced the mRNA level of HMG-CoA synthase in hepatocytes (Bennett et al 1995;Lopez et al 1996). Therefore, the HMG-CoA content in the cholesterol diet group was about 90 % of that in the no-cholesterol diet group, a difference that was without significance, although the cholesterol diet group had a significantly higher SREBP-1 mRNA level than the no-cholesterol diet group.…”

Soy Protein Suppresses Gene Expression of Acetyl-CoA Carboxylase Alpha from Promoter PI in Rat Liver

“…10,11) SREBP-1 binds to the sterol regulatory element in the ACC PII promoter to enhance the transcription of PIIgenerated ACC mRNA. 12) Since dietary soy protein reduces SREBP-1 protein content in hepatic nuclei, 5) expression of ACC mRNA generated from PII promoter is presumed to be specifically down-regulated by this alteration in SREBP-1.…”

Protein Tyrosine Phosphatase 1B Reduction Regulates Adiposity and Expression of Genes Involved in Lipogenesis

“…One of the transcription factors that has been shown to regulate the expression of several key genes of fatty acid and triglyceride metabolism is sterol regulatory element-binding protein (SREBP)1 (12). The family of SREBP-responsive genes, first limited to the LDL receptor and genes involved in cholesterol synthesis, has been expanded to include several additional genes that control lipid metabolism, such as fatty acid synthase (FAS) (13), acetyl-CoA carboxylase (14), glycerol-3-phosphate acyltransferase (15), leptin (16), and lipoprotein lipase (LPL) (17), which are important for adipose tissue metabolism. SREBPs have also been implicated in the enlargement of adipocyte energy stores and obesity (13).…”