Overproduction of Very Low–Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome

Abstract

Insulin resistance is a key feature of the metabolic syndrome and often progresses to type 2 diabetes. Both insulin resistance and type 2 diabetes are characterized by dyslipidemia, which is an important and common risk factor for cardiovascular disease. Diabetic dyslipidemia is a cluster of potentially atherogenic lipid and lipoprotein abnormalities that are metabolically interrelated. Recent evidence suggests that a fundamental defect is an overproduction of large very low–density lipoprotein (VLDL) particles, which initiates a sequence of lipoprotein changes, resulting in higher levels of remnant particles, smaller LDL, and lower levels of high-density liporotein (HDL) cholesterol. These atherogenic lipid abnormalities precede the diagnosis of type 2 diabetes by several years, and it is thus important to elucidate the mechanisms involved in the overproduction of large VLDL particles. Here, we review the pathophysiology of VLDL biosynthesis and metabolism in the metabolic syndrome. We also review recent research investigating the relation between hepatic accumulation of lipids and insulin resistance, and sources of fatty acids for liver fat and VLDL biosynthesis. Finally, we briefly discuss current treatments for lipid management of dyslipidemia and potential future therapeutic targets.

Non-dipping pattern in ambulatory blood pressure monitoring is associated with metabolic abnormalities in a random sample of middle-aged subjects

“…28 The fundamental defect is believed to be the overproduction of large VLDL particles, which initiates a sequence of lipoprotein changes. 30 The mechanism behind the increase of triglyceride-rich particles among non-dippers remains unclear in our study, as it was not related to the obesity or the associated insulin resistance. It has been shown previously that the levels of plasma free fatty acids correlate with glucose tolerance independently of total adiposity.…”

ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD – Summary

“…Increased free fatty acid (FFA) flux comes from both the systemic FFA pools and de novo lipogenesis in the setting of insulin resistance (IR). 138,139 Dyslipidaemia and macrovascular disease. A causal association exists between elevation of triglyceride rich particles, low HDL-C, and CVD risk.…”

Impact of bariatric surgery on apolipoprotein C-III levels and lipoprotein distribution in obese human subjects

“…This improvement was manifested by decreased production of VLDL and chylomicrons and increased clearance of VLDL. 33 VLDL and chylomicrons are overproduced in insulin-resistant subjects compared with healthy controls, 6,7,[43][44][45][46] and this overproduction seems to result, in part, from decreased sensitivity to the acute inhibitory effect of insulin on Table 2 Mean presurgery (M0) and postsurgery evolution at 6 months (M6) and at 12 months (M12) of weight, BMI, insulin resistance, adiponectin, energy expenditure, and energy intake in the GBP and SG groups of obese subjects Table 4 Mean presurgery (M0) and postsurgery evolution at 6 months (M6) and at 12 months (M12) of apoC-II and apoC-III in HDL and non-HDL fractions in the GBP and SG groups of obese subjects VLDL and chylomicron secretion. 5 Moreover, reduced activity of LPL has been shown in insulin-resistant subjects compared with control subjects in fasting and postprandial states.…”

“…5 The pathophysiology of this dyslipidemia is widely explained by the blood accumulation of triglyceride-rich lipoproteins (TRL) from liver (very-low-density lipoprotein [VLDL]) and intestine (chylomicrons) origin. This accumulation has been attributed to the overproduction of both VLDL 6 and chylomicrons 7 and to a defective TRL removal process because of a number of associated mechanisms: reduction of lipoprotein lipase (LPL) activity, 8 changes in the apolipoprotein composition of TRL 9 impairing particle clearance, and defect in the hepatic uptake of TRL and their remnants. 8 Apolipoprotein C-III (apoC-III) is synthesized by the liver and to a lesser extent by the intestine.…”