Liver cholesterol biosynthesis

Scallen, T. J., Seetharam, B., Srikantaiah, M. V., Hansbury, E., and Lewis, M. K., 1975, Sterol carrier hypothesis Requirement for three substrate-specific soluble proteins in liver cholesterol biosynthesis. Life Sci. 16 853. 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

The fact that raising the number of active LDL receptors on liver cells with inhibitors of cholesterol biosynthesis does not decrease Lp(a) concentrations would support this notion (K29, W13). 

Liver microsomal enzymes of cholesterol biosynthesis have been shown to be stimulated 4-fold or more by an activator isolated from the... 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

The statin family of six closely related hypocholesterolemic drugs are all potent competitive inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis. The liver is their target organ, and decreased hepatic cholesterol synthesis ultimately leads to increased removal of LDL particles from the circulation. As a consequence, all other hypocholesterolemic drugs have been relegated to secondary status. 

Mechanism of Action An HMG-CoA reductase inhibitor that interferes with cholesterol biosynthesis by preventing the conversion of HMG-CoA reductase to meva-lonate, a precursor to cholesteroh Therapeutic Effect Lowers serum LDL and VLDL cholesterol and plasma triglyceride levels increases serum HDL concentration. Pharmacokinetics Poorly absorbed from the G1 tract. Protein binding 50%. Metabolized in the liver (minimal active metabolites). Primarily excreted in feces via the biliary system. Not removed by hemodialysis. Half-life 2.7 hr. 

Cholesterol is a soft waxy substance that is a steroidal alcohol or sterol. It is the most abundant steroid in the human body and is a component of every cell. Cholesterol is essential to life and most animals and many plants contain this compound. Cholesterol biosynthesis occurs primarily in the liver, but it may be produced in other organs. A number of other substances are synthesized from cholesterol including vitamin D, steroid hormones (including the sex hormones), and bile salts. Cholesterol resides mainly in cell membranes. 

Regulation of Cholesterol Biosynthesis Cholesterol in humans can be obtained from the diet or synthesized de novo. An adult human on a low-cholesterol diet typically synthesizes 600 mg of cholesterol per day in the liver. If the amount of cholesterol in the diet is large, de novo synthesis of cholesterol is drastically reduced. How is this regulation brought about ... 

The thiolase and HMG-CoA synthase exhibit some regulatory properties in rat liver (cholesterol feeding causes a decrease in these enzyme activities in the cytosol but not in the mitochondria). However, the primary regulation of cholesterol biosynthesis appears to be centered on the HMG-CoA reductase reaction. HMG-CoA reductase is found on the endoplasmic reticulum, has a molecular weight of 97,092, and consists of 887 amino acids in a single polypeptide chain. The sequence of the enzyme was deduced by Michael Brown and Joseph Goldstein from the sequence of a piece of complimentary DNA (cDNA) derived from mRNA that codes for the reductase. The enzyme... 

The material (H) has been tested with preparations of rat liver hepatocytes and has been found to enter them and to serve as an inhibitor of cholesterol biosynthesis therein. Using (H) bearing a specific radiocarbon label, studies have been performed in intact animals. The material has been injected IV and found to be cleared from the blood rapidly, the major portion being delivered to the liver. Small portions are found in bile and intestine, but not in other organs of the animals. 

Steiner S, Gatlin CL, Lennon JJ, McGrath AM, Seonarain MD, Makusky AJ, Aponte AM, Esquer-Blasco R, Anderson NL. Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin. Toxicol Lett 2001 120 369-377. 

Cholesterol can either be obtained in the diet or synthesized in the liver. High levels of cholesterol and its metabolites decrease the amount and inhibit the activity of HMG CoA reductase, the enzyme that catalyzes the committed step in cholesterol biosynthesis. This enzyme can also be inhibited therapeutically... 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Cholesterol can be obtained either from the diet or it can be synthesized de novo, mainly in the liver. Cholesterol is transported round the body in lipoprotein particles (see Topic K6). The rate of synthesis of cholesterol is dependent on the cellular level of cholesterol. High levels of cholesterol and its metabolites control cholesterol biosynthesis by ... 

Figure 19.12 Regulation of liver acetyl-CoA carboxylase and cholesterol biosynthesis by phosphorylation. ACC indicates acetyl-CoA carboxylase. Bold arrow indicates activation of kinase kinase by fatty acyl-CoA. (Reproduced by permission from Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multi-substrate regulator of lipid metabolism. Trends Biochem Sci 14 20-23, 1989.)...

A feedback mechanism operates in which intracellular free cholesterol inhibits HMG-CoA reductase. When the diet is rich in cholesterol, intracellular cholesterol increases in the liver and the biosynthesis of cholesterol is suppressed. Conversely, a low-cholesterol diet, but one with adequate triglyceride, stimulates cholesterol biosynthesis. 

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