My answer to What dictates how much cholesterol is produced by your body?
Answer by Connie b. Dellobuono:
Due to its important role in membrane function, all cells express the enzymes of cholesterol biosynthesis.
Cholesterol ester transfer protein (CETP) is secreted primarily from the liver and plays a critical role in HDL metabolism by facilitating the exchange of cholesteryl esters (CE) from HDL for triglycerides (TG) in apoB containing lipoproteins, such as LDL and VLDL. The activity of CETP directly lowers the cholesterol levels of HDLs and enhances HDL catabolism by providing HDLs with the TG substrate of hepatic lipase. Thus, CETP plays a critical role in the regulation of circulating levels of HDL, LDL, and apoA-I. It has also been shown that in mice naturally lacking CETP most of their cholesterol is found in HDL and these mice are relatively resistant to atherosclerosis.
Slightly less than half of the cholesterol in the body derives from biosynthesis de novo. Biosynthesis in the liver accounts for approximately 10%, and in the intestines approximately 15%, of the amount produced each day. The cholesterol biosynthesis pathway involves enzymes that are in the cytoplasm, microsomes (ER), and peroxisomes. Synthesis of cholesterol, like that of most biological lipids, begins from the two-carbon acetate group of acetyl-CoA.
The process of cholesterol synthesis can be considered to be composed of five major steps:
1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
2. HMG-CoA is converted to mevalonate
3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2
4. IPP is converted to squalene
5. Squalene is converted to cholesterol.
Through a series of 19 additional reactions, lanosterol is converted to cholesterol. These 19 reaction steps are catalyzed by nine different enzymes that are localized either to the ER or to the peroxisomes. The terminal reaction in cholesterol biosynthesis is catalyzed by the enzyme 7-dehydrocholesterol reductase encoded by the DHCR7 gene. Functional DHCR7 protein is a 55.5 kDa NADPH-requiring integral membrane protein localized to the microsomal (ER) membrane. The DHCR7 gene is located on chromosome 11q13.4 and is composed of 9 exons that generate two alternatively spliced mRNAs, both of which encode the same 475 amino acid protein. Deficiency in DHCR7 (due to gene mutations) results in the disorder called Smith-Lemli-Opitz syndrome, SLOS. SLOS is characterized by increased levels of 7-dehydrocholesterol and reduced levels (15% to 27% of normal) of cholesterol resulting in multiple developmental malformations and behavioral problems.
Normal healthy adults synthesize cholesterol at a rate of approximately 1g/day and consume approximately 0.3g/day. A relatively constant level of cholesterol in the blood (150–200 mg/dL) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Cholesterol from both diet and synthesis is utilized in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis.
The cellular supply of cholesterol is maintained at a steady level by three distinct mechanisms:
1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular free cholesterol through the activity of sterol O-acyltransferases, SOAT1 and SOAT2 with SOAT2 being the predominant activity in liver. The original designation for these enzymes was ACAT for acyl-CoA: cholesterol acyltranferase. However, this conflicts with the official ACAT enzymes, ACAT1 and ACAT2 which are acetyl-CoA acetyltransferases 1 and 2. These latter two enzymes are thiolases discussed in the Lipolysis and Fatty Acid Oxidation page.
3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-mediated reverse transport.
Since the intracellular level of cAMP is regulated by hormonal stimuli, regulation of cholesterol biosynthesis is hormonally controlled. Insulin leads to a decrease in cAMP, which in turn activates cholesterol synthesis. Alternatively, glucagon and epinephrine, which increase the level of cAMP, inhibit cholesterol synthesis.
The ability of insulin to stimulate, and glucagon to inhibit, HMGR activity is consistent with the effects of these hormones on other metabolic pathways. The basic function of these two hormones is to control the availability and delivery of energy to all cells of the body.
Long-term control of HMGR activity is exerted primarily through control over the synthesis and degradation of the enzyme. When levels of cholesterol are high, the level of expression of the HMGR gene is reduced. Conversely, reduced levels of cholesterol activate expression of the gene. Insulin also brings about long-term regulation of cholesterol metabolism by increasing the level of HMGR synthesis.
Liver:
Cytochrome P450 Enzymes in Cholesterol Metabolism
Cytochrome P450 enzymes are involved in a diverse array of biological processes that includes lipid, cholesterol, and steroid metabolism as well as the metabolism of xenobiotics. The now common nomenclature used to designate P450 enzymes is CYP. There are at least 57 CYP enzymes in human tissues with eight being involved in cholesterol biosynthesis and metabolism, which includes conversion of cholesterol to bile acids. CYP metabolism of cholesterol yields several oxysterols that function as biologically active molecules such as in the activation of the liver X receptors (LXRs) and SREBP (see the next section).
Sterol control of transcription affects more than 30 genes involved in the biosynthesis of cholesterol, triacylglycerols, phospholipids and fatty acids.
Synthesis, Metabolism, Regulation
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What dictates how much cholesterol is produced by your body?
