Cp-346086

Abstract

41%, of all deaths in the United States in 1998 (1). As a consequence of atherosclerosis, coronary heart disease (CHD) is the most common cause of cardiovascular morbidity and mortality, with an estimated 12 million people suffering from CHD in the United States alone (1). Elevated total and LDL cholesterol are both accepted primary risk factors for atherosclerosis (1-3). An estimated 101 million United States adults have elevated blood cholesterol ( Ͼ 200 mg/dl) and are candidates for LDL cholesterol lowering through dietary intervention (1, 4, 5). Of these, 41 million are considered high risk, having blood cholesterol greater than 240 mg/dl, and drug therapy is recommended (1, 4, 5).Epidemiological studies have shown that elevated triglycerides and reduced HDL cholesterol are also contributing factors for the development of CHD (2, 3, 6-8). Among the adult United States population, 19% of people have low HDL cholesterol ( Ͻ 40 mg/dl) (3, 9, 10) and 21% have hypertriglyceridemia ( Ͼ 150 mg/dl) (3, 10). Thus, as important as elevated LDL cholesterol is as a risk factor for CHD, it is important to recognize that the most common spectrum of lipid abnormalities is atherogenic dyslipidemia, which is present in 45-50% of men with CHD (11, 12) and includes borderline high-risk LDL cholesterol (e.g., 130-159 mg/dl), elevated triglycerides, small dense LDL particles, and low HDL cholesterol.The HMG-CoA reductase inhibitors (statins) are very effective in lowering LDL cholesterol and somewhat effective in reducing triglycerides, but they have only minimal effects on HDL cholesterol (2, 5, 13-15). Indeed, although numerous clinical trials have demonstrated that LDL cholesterol reduction can significantly reduce CHD risk, a great number of treated subjects who achieve substantial LDL cholesterol reduction still experience a clinical event (2,3,(13)(14)(15)(16)(17)(18). Therefore, with the goal of developAbbreviations: CETP, cholesterol ester transfer protein; CHD, coronary heart disease; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein.

Microsomal Triglyceride Transfer Protein Enhances Cellular Cholesteryl Esterification by Relieving Product Inhibition

“…Pharmacologic interventions to reduce MTP result in hepatosteatosis and enhanced plasma concentrations of liver enzymes (35,61). The mechanistic studies described here indicate that the toxicity associated with blocking MTP activity might result from the accumulation of free cholesterol.…”

Coordinate Transcriptional Repression of Liver Fatty Acid-binding Protein and Microsomal Triglyceride Transfer Protein Blocks Hepatic Very Low Density Lipoprotein Secretion without Hepatosteatosis

“…Our findings have important implications regarding the efficacy of MTP inhibitors to ameliorate hyperlipidemia (47)(48)(49)(50). In a recent study, treatment of hyperlipidemic apoE knock-out mice with an MTP inhibitor caused a marked reduction in both plasma lipids and the progression of atherosclerosis (64).…”

“…Vivo-Chemical inhibition of MTP, a strategy developed to ameliorate hyperlipidemia (47)(48)(49)(50), is of limited use because of the development of hepatic steatosis (35,51). Although L35 cells do not express MTP or secrete apoBcontaining lipoproteins, they do not accumulate triglycerides even when challenged with fatty acids (e.g.…”

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

“…Long-term treatment with MTP inhibitors led to the accumulation of fat in livers (39). However, short-term treatment (up to several weeks) reduced the level of VLDL with only minor adverse effects, which disappeared after drug removal (39).…”

“…Antisense RNA drugs targeting apoB (37) and several MTP inhibitors have already been tested in clinical trails because of their ability to block VLDL secretion, thereby lowering the level of plasma triglyceride and LDL cholesterol (38,39). Long-term treatment with MTP inhibitors led to the accumulation of fat in livers (39).…”