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Nuclear

Adenine UraciK

Guanine-''' Cytosine mRNA 1'-Transcript

Introns

Introns

Cap Tail-AAAA

Cap Tail-AAAA

Cap mRNA Tail

membrane

5' Mature mRNA 3

Small ribosome

Figure 2 Schematic view of transcription.

metallothionein, which binds zinc and may play a key role in zinc homeostasis.

The direct binding of a nutrient signal to a transcription factor is perhaps one of the simpler ways in which nutrients impact gene transcription. There are other less direct but equally important mechanisms. Genes involved in cholesterol homeostasis are characterized by a sterol response element (SRE) in their promoter regions, which interacts with a sterol response element binding protein (SREBP). This protein is synthesized as a large precursor, incorporated into endoplasmic reticulum membranes, and is unavailable to function in gene regulation until it is cleaved and released. Limited cholesterol availability results in the cleavage and release of SREBP from the membrane compartment and its translocation to the nucleus. There it can perform its gene regulatory function by activating the transcription of genes for cholesterol synthesis as well as the LDL receptor gene. The LDL receptor facilitates cholesterol uptake by the liver. When it is abnormal due to a mutation in its gene, hypercholesterolemia results. The liver is unable to remove cholesterol from the blood and continues to synthesize it since SREBP remains active.

The metabolism and availability of macro-nutrients also influence gene transcription. Promoter elements have been described that allow a response to glucose (the carbohydrate response element (CHORE)). Although the specifics are unclear, the activity of the protein that binds this element responds to the metabolism of glucose and then stimulates the transcription of relevant genes—for example, those required for glucose metabolism (pyruvate kinase) and fatty acid synthesis (acetyl-coA carboxylase and fatty acid synthase). Fatty acids also influence gene expression. They can affect transcription by binding directly to their own transcription factor (the peroxisome proliferator activated receptor) and also indirectly by reducing the availability of SREBP within the nucleus. The latter mechanism provides a means for linking cholesterol and fatty acid metabolism with the cell.

Nutrients can also affect gene expression indirectly by regulating the release of hormones into the blood. Thus, glucose, in addition to having its own effects on gene expression through the CHORE, also stimulates insulin secretion from the pancreas. Insulin has its own transcriptional effects, often on the same genes that are regulated by glucose. In the postabsorptive state, insulin drops and glucagon is released. This hormone activates an intracellular signaling pathway that results in inhibition of genes involved in glucose metabolism and fatty acid synthesis and stimulation of genes involved in gluconeogenesis (e.g., phosphenolpyruvate car-boxykinase). Taken as a whole, macronutrient availability regulates the expression of the complex set of genes responsible for macronutrient metabolism by an aggregate of direct and endocrine-mediated pathways.

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