Direct Regulatory Effect of Fatty Acids on Macrophage Lipoprotein Lipase

Abstract

Atherosclerosis is a major complication of type 2 diabetes. The pathogenesis of this complication is poorly understood, but it clearly involves production in the vascular wall of macrophage (Mo) lipoprotein lipase (LPL). Mo LPL is increased in human diabetes. Peripheral factors dysregulated in diabetes, including glucose and free fatty acids (FAs), may contribute to this alteration. We previously reported that high glucose stimulates LPL production in both J774 murine and human Mo. In the present study, we evaluated the direct effect of FAs on murine Mo LPL expression and examined the involvement of peroxisome proliferator-activated receptors (PPARs) in this effect. A therosclerosis is the major underlying cause of cardiovascular diseases in adults and the leading cause of morbidity and mortality among diabetic patients (1-6). It has been shown that lipoprotein lipase (LPL), a secretory product of macrophage (Mo) in the arterial wall, contributes to the development and progression of atherosclerosis (7-12). We have previously shown that high glucose enhances LPL production in J774 murine and human Mo (13). Furthermore, we have recently demonstrated that Mo isolated from patients with type 2 diabetes overproduce LPL (14). Besides glucose, other metabolic factors dysregulated in diabetes, such as fatty acids (FAs), may play a key role in the Mo LPL overproduction associated with human diabetes. Indeed, FAs are increased in the plasma of diabetic patients and are produced at high concentrations in the arterial wall through the hydrolysis of triglyceride-rich lipoproteins infiltrating the intima (15).The role of FAs in atherogenesis has been largely characterized over the last decade. Whereas much evidence supports a proatherogenic effect of saturated , a protective action with respect to the arterial wall has been attributed to unsaturated . Lipid metabolism is one major mechanism responsible for the modulatory effect of FAs on the atherogenic process. LPL is a major enzyme involved in the hydrolysis of lipoproteins. Recently, an inhibitory effect of FAs on plasma and adipocyte LPL has been documented. More specifically, it has been shown that rats fed a high-fat diet have decreased plasma and adipocyte LPL activity levels (26) and that high-fat feeding of normal subjects causes an impairment of insulin-stimulated LPL activity in adipose tissue (27). In addition, fasting and catecholamines, which stimulate lipolysis and increase plasma FA levels, have been reported to decrease adipocyte LPL activity (28). Because LPL gene expression in adipose tissue is increased (29) or unaffected by FAs (30,31), posttranslational mechanisms have been implicated in the regulation of adipocyte LPL by these metabolic agents.From the

Homocysteine Induces Protein Kinase C Activation and Stimulates c-Fos and Lipoprotein Lipase Expression in Macrophages

“…The regulation of Mo LPL in the arterial wall is poorly understood but may involve metabolic factors. This hypothesis is supported by our previous findings that Mo LPL is increased in patients with type 2 diabetes (30) and that metabolic factors dysregulated in diabetes, such as glucose (31) and fatty acids (32), enhance Mo LPL expression. On the basis of these findings and of the high levels of serum Hcys in patients with diabetes, we sought to evaluate the direct regulatory effect of Hcys on Mo LPL expression and to determine the molecular mechanism(s) involved in this effect.…”

PPAR-α effects on the heart and other vascular tissues

“…Although active in inhibiting apo C-III in rodents, the ability of PPAR-␣ agonists to lower apo C-III in humans remains controversial (38,50). PPAR-␣ agonists may also decrease TG levels by increasing the expression of LPL in the liver (77) and in macrophages (2,60). How much of the hypotriglyceridemic effect of PPAR-␣ ligands can be ascribed to direct versus indirect effects (via decreased apo C-III) on LPL is not yet known.…”

“…The heart also expresses LPL, which has been found to be upregulated in the liver and macrophages in response to PPAR-␣ agonists (60,77). Although likely a key player in myocardial TG hydrolysis and fatty acid uptake, cardiac LPL activity has been found to be inhibited by PPAR-␣ agonists in cultured rat cardiomyocytes (12).…”

Association of lipoprotein lipase gene polymorphisms with obesity and type 2 diabetes in an Asian Indian population

“…14 This activation occurs by the binding of PPARg and the 9-cis retinoic acid receptor (RXR) heterodimers to the PPAR response element (PPRE) sequence (À169 TGCCCTTTCC CCC À157) in the promoter of the LPL gene. 15,16 Important cis-acting elements in the promoter of LPL gene have been identified that bind DNA-binding proteins and appear to confer basal and/or ligand-mediated LPL gene transcription. 17 DNA variants in the promoter of the LPL gene have been shown to be associated with changes in lipid metabolism leading to type 2 diabetes and its related traits.…”