COMPLETED SEARCH AND RESEARCH MISSION

Here is a summary of the 'Mission and links'.

1. Bile Acid Sequestrants

Bile acid sequestrants are synthetic polymeric compounds which serve as ion exchange resins, exchanging anions such as chloride ions for bile acids so that they bind bile acids and sequester them from enterohepatic circulation and thus preventing reabsorption from the digestive tract. Since bile acid sequestrants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream, thereby bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract. Since bile acids are biosynthesized from cholesterol, the disruption of bile acid reabsorption will decrease cholesterol levels, particularly low density lipoprotein (commonly known as "bad cholesterol").

2. Fibric Acid Derivatives

Fibric acid derivatives are produced by several fungi. Fibric Acid Derivatives have a complex mechanism of action, involving several steps in the metabolism of lipoproteins. In particular, the activity of lipoprotein lipase is increased and synthesis of apoC-III is decreased, which both enhance the clearance of circulating triglyceride-rich lipoproteins. PPAR activation regulates gene expression involved in metabolic pathways including lipid metabolism, thereby reducing triglyceride concentrations and increasing HDL concentrations.

3. Niacin

NIH Niacin Information

Niacin is a water-soluble B vitamin, produced in the body from tryptophan (niacinamide) and foods high in protein are highest in niacin such as lean meat, liver, fish, poultry, eggs, legumes, peanut butter, and enriched cereals.

New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for triglyceride (TG) synthesis and thereby leading to the inhibition of TG synthesis resulting in decreased secretion of VLDL and LDL particles. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.

4. HMG-CoA reductase enzyme inhibitors

HMG-CoA reductase inhibitors (Statins) lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream. By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver and this is significant because most circulating cholesterol comes from internal manufacture rather than the diet. The first agent isolated was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum. The pharmaceutical company Merck & Co. showed an interest in the Japanese research in 1976, and isolated lovastatin (mevinolin, MK803), the first commercially marketed statin, from the fungus Aspergillus terreus.

5. New Antihyperlipidemic Agents on the Horizon

The pharmacological effect of FR177391, isolated from Serratia liquefaciens No. 1821, was studied in normal animals and various types of animal models of hypertriglyceridemia. FR177391 treatment decreased triglyceride (TG) and increased high-density lipoprotein cholesterol in the blood in normal rats following 7 days treatment. Both Triton WR1339-induced severe and fructose-induced mild hypertriglyceridemia in rats were attenuated by FR177391 treatment. Severely elevated levels of TG in db/db mice, an insulin resistant diabetic animal model, also significantly decreased from 14 days of treatment with FR177391. FR177391 treatment for 9 days caused a decrease in the elevated levels of TG in mice induced by intraperitoneal inoculation of murine lymphoma EL-4. Overall, this study demonstrated that FR177391 can be possibly a LPL activating agent and that FR177391 treatment improved hypertriglyceridemia in various rat and mouse animal models. These results suggest that FR177391 is a promising candidate compound for the management of hypertriglyceridemia.

WHEW!!!!