Humans have two sources of cholesterol: absorption from ingested food and de nov

Question

Humans have two sources of cholesterol: absorption from ingested food and de novo synthesis by the liver High levels of cholesterol in the blood correlates with cardiovascular disease, but cholesterol is required to regulate membrane fluidity and as a precursor for important molecules like steroids and bile acids. Thus, humans evolved several types of regulation of cholesterol levels. How does the human body compensate for excess consumption of cholesterol in the diet? Eating a cholesterol-richmeal causes the hypothalamus, the hunger center of the brain, to signal satiety Excess cholesterol and a lack of ATP inhibit the activity of HMG-CoA reductase in the liver to decrease cholesterol synthesis Transcription ofthe HMG-CoA reductase gene decreases in the presence of high intracellular cholesterol High cholesterol concentrations upregulate the number of serum transport proteins that deliver cholesterol to the liver for degradation. Adipose cells switch to using cholesterol instead of glucose to produce ATP

Explanation / Answer

2) Excess cholesterol and a lack of ATP inhibit the activity of HMG-CoA reductase (HMGR) in the liver to decrease cholesterol synthesis. Cholesterol involves in feed-back inhibition of HMGR and induction of rapid degradation of this enzyme by the cholesterol-induced polyubiquitylation and proteosomal degradation. Inhibition by cholesterol is due to the presence of sterol sensing domain, SSD of HMGR. HMGR activity is decreased by phosphorylation and so this enzyme is inactivated by an AMP-activated protein kinase. Thus, cholesterol synthesis is inhibited when the ATP level is low.

3) Transcription of the HMG-CoA reductase gene decreases in the presence of high intracellular cholesterol. The rate of synthesis of HMGR mRNA is regulated by the sterol regulatory element binding protein (SREBP), a transcription factor that binds to a short DNA sequence called the sterol regulatory element (SRE) on the 5 side of the HMGR gene. When this enzyme is inactive, the SREBP is anchored to the endoplasmic reticulum or nuclear membrane. When cholesterol levels decrease, the amino-terminal domain is released from its association with the membrane by two specific proteolytic cleavages. The released protein then migrates to the nucleus and binds the SRE of the HMGR gene to enhance transcription. When cholesterol levels rise, the proteolytic release of the SREBP is blocked, and the SREBP in the nucleus is rapidly degraded inhibiting the transcription of the genes of the cholesterol biosynthetic pathways.

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