Effects of glucose metabolism on the regulation of genes of fatty acid synthesis and triglyceride secretion in the liver

Abstract

Glucose disposal induces a signal that modulates the transcriptional regulation of genes involved in the glycolysis and lipogenesis pathways. To investigate the role of glucose metabolism on hepatic gene expression independently from insulin action, we overexpressed glucokinase, the limiting enzyme in the glycolysis pathway, in the liver of streptozotocin-induced type 1 diabetic rats. By microarray analysis, we observed that critical genes such as livertype pyruvate kinase, malic enzyme, fatty acid synthase, and stearoyl-CoA desaturase 1 were enhanced multiple-fold, whereas genes involved in mitochondrial fatty acid oxidation and the Krebs cycle were downregulated. Despite the increase in expression of fatty acid synthesis genes and the presence of steatosis, no major alterations to the levels of genes involved in VLDL assembly and secretion, such as diacylglycerol acyltransferases 1 and 2 and microsomal triglyceride transfer protein, were observed. Overall, our data suggest that the gene expression pattern induced by glucose metabolism favors fatty acid storage in the liver rather than secretion into the circulation.-Morral, N., H. J. Edenberg, S. R. Witting, J. Altomonte, T. Chu, and M. Brown. Effects of glucose metabolism on the regulation of genes of fatty acid synthesis and triglyceride secretion in the liver. J. Lipid Res.

Hepatocyte-specific IKK-β activation enhances VLDL-triglyceride production in APOE*3-Leiden mice

“…The fact that activation of NF-B has been linked to local disturbances in glucose metabolism that could activate ChREBP would underscore this observation ( 1,34,35 ). It is thus conceivable that increased ChREBP-mediated Fas expression increases hepatic lipogenesis and thereby increases lipid availability for VLDL-TG production ( 36 ). In fact, activation of lipogenesis results in large, but not more, VLDL particles, which is consistent with our fi ndings ( 37 ).…”

Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer

“…It has also been shown that human de novo FA synthesis is stimulated by a eucaloric low-fat/high-carbohydrate diet (28 ), and that lean as well as obese individuals fed a low-fat/highcarbohydrate diet have increased levels of hepatic de novo lipogenesis compared with individuals fed a highfat/low-carbohydrate diet (29 ). In fact, because glucose is constantly required at a high rate by multiple tissues, mammals have evolved mechanisms to sense glucose levels and adapt the expression of genes to glucose availability and to adapt their metabolism to the nutritional environment (30 ). When abundant food supplies are accessible, nutrients are stored for subsequent use during periods of food shortage.…”

The effects of diet composition and vitamin B supplementation on the urine isoprostane concentration in rats

“…The question why increased deposition of fat in the liver was not observed in the group of animals supplemented in the excessive mode still remains open. An expected outcome of the significantly higher plasma level of glucose, determined in this group of animals, should be an increase in the fat content of the liver, because studies (Morral et al, 2007) have demonstrated that in liver, hyperglycaemia causes the overexpression of a glucokinase gene, expression of genes of lipogenesis enzymes, and simultaneously suppresses the expression of genes taking part in fatty acid oxidation. On the other hand, however, the supplementation with niacin might have caused diminished esterification of fatty acids to triacylglycerols through an effect on mRNA expression and microsomal activity of diacylglycerol acyltransferase 2 (DGAT2) (Ganiji et al, 2004).…”