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, 5 (4), 1218-40

Dyslipidemia in Obesity: Mechanisms and Potential Targets


Dyslipidemia in Obesity: Mechanisms and Potential Targets

Boudewijn Klop et al. Nutrients.


Obesity has become a major worldwide health problem. In every single country in the world, the incidence of obesity is rising continuously and therefore, the associated morbidity, mortality and both medical and economical costs are expected to increase as well. The majority of these complications are related to co-morbid conditions that include coronary artery disease, hypertension, type 2 diabetes mellitus, respiratory disorders and dyslipidemia. Obesity increases cardiovascular risk through risk factors such as increased fasting plasma triglycerides, high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels and high blood pressure. Novel lipid dependent, metabolic risk factors associated to obesity are the presence of the small dense LDL phenotype, postprandial hyperlipidemia with accumulation of atherogenic remnants and hepatic overproduction of apoB containing lipoproteins. All these lipid abnormalities are typical features of the metabolic syndrome and may be associated to a pro-inflammatory gradient which in part may originate in the adipose tissue itself and directly affect the endothelium. An important link between obesity, the metabolic syndrome and dyslipidemia, seems to be the development of insulin resistance in peripheral tissues leading to an enhanced hepatic flux of fatty acids from dietary sources, intravascular lipolysis and from adipose tissue resistant to the antilipolytic effects of insulin. The current review will focus on these aspects of lipid metabolism in obesity and potential interventions to treat the obesity related dyslipidemia.


Figure 1
Figure 1
The hallmark of dyslipidemia in obesity is hypertriglyceridemia in part due to increased free fatty acid (FFA) fluxes to the liver, which leads to hepatic accumulation of triglycerides (TG). This leads to an increased hepatic synthesis of large very low density lipoproteins (VLDL) 1, which hampers the lipolysis of chylomicrons due to competition mainly at the level of lipoprotein lipase (LPL) with increased remnant TG being transported to the liver. Lipolysis is further impaired in obesity by reduced mRNA expression levels of LPL in adipose tissue and reduced LPL activity in skeletal muscle. Hypertriglyceridemia further induces an increased exchange of cholesterolesters (CE) and TG between VLDL and HDL and low density lipoproteins (LDL) by cholesterylester-transfer-protein (CETP). This leads to decreased HDL-C concentrations and a reduction in TG content in LDL. In addition, hepatic lipase (HL) removes TG and phospholipids from LDL for the final formation of TG-depleted small dense LDL. The intense yellow color represents cholesterol, whereas the light yellow color represents the TG content within the different lipoproteins. Obesity induced increases in metabolic processes are marked with green arrows, whereas reductions are marked with red arrows.
Figure 2
Figure 2
Free fatty acid (FFA) uptake and its related triglyceride (TG) synthesis in adipocytes are highly depended of C3adesArg or acylation-stimulation protein (ASP). Chylomicrons and VLDL undergo lipolysis by lipoprotein lipase (LPL) with subsequent release of FFA into the circulation. The FFA are then transported into the subendothelial space by the scavenger receptor CD36 and other transporters where C3adesArg plays an important role in the subsequent TG synthesis for storage of lipids in the adipocytes. C3adesArg is the most potent molecule known, which induces transmembrane transport of FFA and its intracellular esterification into TG within adipocytes. C3adesArg is metabolized from complement component (C) 3a by carboxypeptidase N and C3a is again the splice product from C3, which is formed in case of complement activation. Postprandial lipemia is directly linked to complement activation. For example, adipocytes secrete C3 when incubated with TG-rich lipoproteins like chylomicrons or very low density lipoproteins (VLDL), but also Factor B and Factor D, thereby causing activation of the complement cascade.

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