Triglycerides, tissue uptake

The metabolism of lipid emulsions has long been considered to be similar to that of chylomicrons with intravascular lipolysis by lipoprotein lipase (LPL) being followed by tissue uptake of remnant particles. However, other studies have suggested that lipid emulsions are cleared from blood with less lipolysis than chylomicrons and that a substantial number of emulsions can be cleared as almost intact whole particles by different tissues. The metabolism of lipid emulsions is affected by many factors, including triglyceride (TG) composition. For example, MCT LCT emulsions are cleared faster from blood than pure LCT emulsions. Recently, it was reported that pure FO emulsion particles are removed from blood faster and by different pathways as compared with LCT emulsions. Removal of LCT emulsions is modulated by LPL, apolipoprotein E (apoE), LDL receptor (LDL-R), and lactoferrin-sensitive pathways. In contrast, clearance of FO emulsions relies on LPL to a much lesser extent and is apparently independent of apoE, LDL-R, and lactoferrin-sensitive pathways. It can therefore be noted that the materials selecteds to develop a nanoemulsion composition may not only affect the physicochemical properties and stability of the formulation but may alter significantly the biofate and efficacy of the nanoemulsions. 

K. Qi, M. Al-Haideri, T. Seo, Y. A. Carpentier and R. J. Deckelbaum, Effects of particle size on blood clearance and tissue uptake of lipid emulsions with different triglyceride compositions. /. Parenter. Enteral. Nutr., 27,58-64 (2003). 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

Metformin is the only biguanide available in the United States. It enhances insulin sensitivity of both hepatic and peripheral (muscle) tissues. This allows for increased uptake of glucose into these insulin-sensitive tissues. Metformin consistently reduces A1C levels by 1.5% to 2%, FPG levels by 60 to 80 mg/dL, and retains the ability to reduce FPG levels when they are very high (>300 mg/dL). It reduces plasma triglycerides and low-density lipoprotein (LDL) cholesterol by 8% to 15% and modestly increases high-density lipoprotein (HDL) cholesterol (2%). It does not induce hypoglycemia when used alone. 

Lipase Inhibitor Orlistat (Xenical, Roche) is prescribed for the treatment of obesity. It inhibits the gastrointestinal lipase enzymes by binding to the lipase through the serine site and inactivates the enzyme. Fat in the form of triglycerides cannot be hydrolyzed by the lipase and converted to free fatty acids and monoglycerides. Thus, there is no uptake of fat molecules into the cell tissue. 

Il.f.l.1. Insulins. Insulin is the most effective of diabetes medications. Insulin has profound effects on carbohydrate, protein, fat metabolism and electrolytes. It has anabolic and anticatabolic actions. In a state of insulin deficiency, glycogenesis, glucose transport, protein synthesis, triglyceride synthesis, LPL activity in adipose tissue, cellular potassium uptake all decrease on the other hand, gluconeogene-sis, glycogenolysis, protein degradation, ketogene-sis, lipolysis increase. 

Mechanism of Action Afibricacid derivative that inhibits lipolysis of fat in adipose tissue decreases liver uptake of free fatty acids and reduces hepatic triglyceride production. Inhibits synthesis of VLDL carrier apolipoprotein B. Therapeutic Effect Lowers serum cholesterol and triglycerides (decreases VLDL, LDL increases HDL). Pharmacokinetics Well absorbed from the GI tract. Protein binding 99%. Metabolized in liver. Primarily excreted in urine. Not removed by hemodialysis. Half-life 1.5 hr. 

Increased synthesis of lipid or uptake. Increased synthesis of lipid may be the cause of fatty liver after hydrazine administration as this compound increases the activity of the enzyme involved in the synthesis of diglycerides. Hydrazine also depletes ATP and, however, inhibits protein synthesis. Large doses of ethanol will cause fatty liver in humans, and it is believed that this is partly due to an increase in fatty acid synthesis. This is a result of an increase in the NADH/NAD"1" ratio and therefore of the synthesis of triglycerides. Changes in the mobilization of lipids in tissues followed by uptake into the liver can also be another cause of steatosis. 

However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver s extraction of LDL precursors (VLDL remnants), thus reducing plasma LDL (Figure 35-2). Because of marked first-pass hepatic extraction, the major effect is on liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Limited reduction of LDL levels in patients who lack functional LDL receptors indicates that decreases in de novo cholesterologenesis also contribute to cholesterol reduction. Modest decreases in plasma triglycerides and small increases in HDL also occur. 

Mendelson, C.R., Scow, R.O. 1972. Uptake of chylomicron-triglyceride by perfused mammary tissue of lactating rats. Am. J. Physiol. 223, 1418-1423. 

The LDL particle (10% triglyceride content) is finally taken up into the liver and other tissues by the LDL receptor. The LDL receptor is a six-domain transmembrane protein whose synthesis is under negative feedback regulation, such that when intracellular cholesterol levels are raised, new LDL receptors are not formed, thereby preventing the uptake of further cholesterol from plasma LDL. LDL also inhibits HMG-CoA reductase and hence cholesterol synthesis by negative feedback inhibition. Absence of the LDL receptor leads to hypercholesterol-aemia and atherosclerosis, as there is a decrease in the rate at which LDLs are removed from the plasma. 

With loss of insulin action and an excess of catabolic hormones, hydrolysis of triglycerides is markedly increased, glycerol supply rises and triglyceride turnover in plasma increases with a concomitant increase in ketoacid derived from hepatic oxidation of FFA. Fatty acids are partly oxidized to ketonic compounds. Ketone synthesis increases more than threefold in the state of insulin deficiency as the result of a low insulin/glucagon ratio and a high FFA supply to the liver. At low insulin levels, ketone uptake and utilization of peripheral tissue is also significantly reduced. 

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