The enhanced synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c (sterol-regulatory-element-binding protein 1c). Insulin increases the expression of the SREBP-1c gene in intact liver and in hepatocytes cultured in vitro. To learn the mechanism of this stimulation, we analysed the activation of the rat SREBP-1c promoter and its truncated or mutated congeners driving a luciferase reporter gene in transiently transfected rat hepatocytes. The rat SREBP-1c promoter contains binding sites for LXR (liver X receptor), Sp1, NF-Y (nuclear factor-Y) and SREBP itself. We have found that each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin. Mutation of either the putative LXREs (LXR response elements) or the SRE (sterol response element) in the proximal SREBP-1c promoter reduced the stimulatory effect of insulin by about 50%. Insulin and the LXR agonist TO901317 increased the association of SREBP-1 with the SREBP-1c promoter. Ectopic expression of LXRalpha or SREBP-1c increased activity of the SREBP-1c promoter, and this effect is further enhanced by insulin. The Sp1 and NF-Y sites adjacent to the SRE are also required for full activation of the SREBP-1c promoter by insulin. We propose that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of the SREBP-1c gene in the liver.

Sterol regulatory element-binding proteins (SREBPs) 3 are transcription factors that regulate expression of genes controlling cholesterol homeostasis and de novo fatty acid synthesis (1-7). SREBP-1a and SREBP-1c, which differ only in their first exon, are derived from a single gene through the use of alternative promoters, whereas SREBP-2 is encoded by a separate gene (8). Although there is clearly some functional overlap among the three SREBP isoforms (5), these proteins regulate different metabolic pathways. SREBP-1c preferentially affects transcription of genes that regulate de novo lipid synthesis, whereas SREBP-2 regulates genes involved in cholesterol biosynthesis and metabolism. The SREBP-1a isoform transactivates both lipogenic and cholesterogenic genes (9). In addition, the three SREBP isoforms exhibit differential tissue-specific expression. In replicating tumor cell lines, SREBP-1a constitutes greater than 90% of the SREBP-1 pool; conversely, SREBP-1c is the predominant isoform in liver and adipose tissue (9). Increased hepatic levels of nuclear SREBP-1c are thought to mediate the development of hyperlipidemia in type II diabetes and hyperinsulinemia (10 -12). Nutritional and hormonal factors have been shown to regulate expression of SREBP-1c and its downstream regulatory targets (10,(13)(14)(15). Insulin induces the expression of SREBP-1c mRNA and nascent precursor protein (10,16,17). Glucagon opposes this effect of insulin via its second messenger cAMP (18). Newly synthesized SREBPs contain two transmembrane domains that are embedded in the endoplasmic reticulum (ER) with the NH 2 -and COOH-terminal sequences exposed to the cytoplasm. Following transport from ER to Golgi, the transcriptionally active NH 2 -terminal segments of SREBPs are liberated by two successive cleavages; the first cleavage in the loop extending into the vesicular lumen is carried out by site 1 protease (S1P), and the second cleavage is executed within the NH 2 -proximal transmembrane domain by site 2 protease (S2P).Regulation of post-translational proteolysis has been studied most extensively in the case of SREBP-2 and SREBP-1a, both of which are regulated primarily by sterols. Within the ER, the

The molecular response of the brain to single-dose irradiation was rapid, while its response to fractionated irradiation was slow. This finding is consistent with clinical observations and could be of use when designing strategies to mitigate radiation sequelae.

This article reviews our understanding of effects of thyroid hormone excess and deficiency on hepatic metabolism of FFA, and consequent effects on production, secretion, and metabolism of plasma lipoproteins. In the hyperthyroid state the following alterations are observed. Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA). Esterification of fatty acid to triglyceride (TG) is reduced, as is the secretion of the very low density lipoprotein (VLDL) (including VLDL TG, cholesterol, and apoprotein); this may be due, in part, to decreased concentrations of glycerol-3-phosphate (G3P) in the hepatic cell. In the intact animal or patient, however, serum TG concentration is variable, which may reflect increased adipose tissue lipolysis and elevated concentrations of plasma FFA, which would tend to drive VLDL secretion by the liver. Clearance of the VLDL and its metabolic product, the low density lipoprotein (LDL), is increased, resulting in decreased plasma total and LDL cholesterol. Although high density lipoprotein (HDL) cholesterol may also be reduced, the ratio of LDL/HDL cholesterol is further decreased. The regulatory role of the lipoprotein apoproteins is less clear, but hepatic apolipoprotein (apo) B secretion (required for VLDL) is diminished, while apo-AI secretion (required for HDL) is stimulated, perhaps both reflecting rates of synthesis. Plasma concentrations of apo-AI are variable, dependent on relative rates of secretion and clearance. In the hypothyroid, many of these effects are reversed, which results in hyperlipoproteinemias and greater risk for the development of atherosclerotic cardiovascular disease.

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