Hormonal and nutritional control of lipogenesis

Carbohydrate-rich diets stimulate lipogenesis in the liver by providing the energy and carbons required for it, because insulin secreted after carbohydrate-rich meals triggers the activation of key enzymes in the glycolytic and lipogenic pathways, and because both glucose (independent of insulin) and insulin favor an increment in the concentration of glycolytic and lipo-genic enzymes, and hence of liver lipogenic capacity, through the up-regulation of the expression levels and activity of key transcription factors controlling the transcription of the genes encoding these enzymes. Transcription factors are proteins that, in their active form, modulate the transcription of target genes by binding to specific nucleotide sequences contained in the corresponding gene promoter; from there, they facilitate or impair the consti-tution of the RNA pol II transcriptional initiation complex and hence transcription. Two key transcription factors promoting the expression of glycolytic and lipogenic genes in the liver are sterol regulatory element binding protein 1 (SREBP-1) and carbohydrate response element binding protein (ChREBP) (reviewed in references 54 and 55) (Fig. 4.4). ChREBP is activated as a transcription factor by dephosphoryla-tion of specific serine residues when glucose is abundant in the hepatocyte (a secondary metabolite of glucose, xylulose-5-phosphate, is believed to alosterically activate the protein phosphatase catalyzing ChREBP dephos-phorylation). SREBP-1 is both induced at the transcriptional level and activated (through controlled proteolysis of an inactive precursor) in response to insulin.

Lipogenese Srebp Chrebp Glucose

Fig. 4.4 Transcriptional control of lipogenic genes in hepatocytes. Most lipogenic enzyme genes contain in their gene promoter response elements (ChRE, SRE) for the binding of ChREBP and SREBP-1. These two factors work synergistically to induce transcription of the lipogenic enzyme genes in the presence of glucose and insulin. Insulin induces the expression of SREBP-1 and favors its activation as a transcription factor for lipogenic genes; glucose favors ChREBP activation. Glucagon, through its intracellular mediator cAMP, inhibits ChREBP activity and suppresses SREBP-1 expression. Excess free fatty acids inhibit ChREBP activity, and PUFAs specifically repress the expression and activity of SREBP-1. In this manner, the output of lipogenic enzyme production is integrated to multiple hormonal and nutritional signals. Solid lines indicate effects on transcription of the gene encoding the transcription factor; dotted lines indicate effects on transcription factor activity (adapted from reference 56).

Fig. 4.4 Transcriptional control of lipogenic genes in hepatocytes. Most lipogenic enzyme genes contain in their gene promoter response elements (ChRE, SRE) for the binding of ChREBP and SREBP-1. These two factors work synergistically to induce transcription of the lipogenic enzyme genes in the presence of glucose and insulin. Insulin induces the expression of SREBP-1 and favors its activation as a transcription factor for lipogenic genes; glucose favors ChREBP activation. Glucagon, through its intracellular mediator cAMP, inhibits ChREBP activity and suppresses SREBP-1 expression. Excess free fatty acids inhibit ChREBP activity, and PUFAs specifically repress the expression and activity of SREBP-1. In this manner, the output of lipogenic enzyme production is integrated to multiple hormonal and nutritional signals. Solid lines indicate effects on transcription of the gene encoding the transcription factor; dotted lines indicate effects on transcription factor activity (adapted from reference 56).

Glucose and insulin also favor lipogenesis in WAT. Glucose serves as precursor for glycerol-3-phosphate in adipocytes and it may have an insulin-independent effect stimulating LPL activity in WAT.57 Insulin enhances LPL activity in WAT, promotes GLUT4 translocation to the adipocyte cell membrane and induces the expression of two key lipogenic transcription factors in adipocytes, the above-mentioned SREBP-1 and peroxisome pro-liferator-activated receptor gamma (PPARy) (reviewed in refernce 58). PPARy is an important stimulator of lipogenesis in differentiated WAT and also plays a pivotal role in adipocyte differentiation.59

On the other hand, dietary fats, and particularly PUFAs, decrease lipo-genesis and lipogenic capacity in the liver (Fig. 4.4) and probably also in WAT. This is discussed in more detail in Section 4.5.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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