| BackgroundAtherosclerotic diseases are the leading cause of death in developedcountries and part of developing countries. Epidemiological studies haverevealed the importance of hyperlipidmia as the strongest risk factors forthe disease. And obesity is an independent risk factor for coronary heartdisease (CHD). Since dysfunctions of adipocytes play a key role forobesity, studying functions of adipocytes is of great significance for theprevent and treatment of obesity and CHD. It has been thought thatdysfunctional adipocytes are closedly associated with atherosclerosis.And adipose tissue has also been thought to be the potential target for thetreatment of atherosclerosis recently.Adipose tissue is the largest energy reservoir in the body. It storesexcess energy in form of triacylglycerol. Moreover, adipose tissue is anactive endocrine organ that secretes various adipokines, many of whichmight play significant roles in atherogenesis. Leptin is synthesized andreleased mainly by adipocytes. It has been shown that hyperleptinemiamay involve in the development of atheroscerosis and is an independentrisk factor for cardiovascular diseases. Adipocytes may play a significantrole in cholesterol metabolism in the body. Adipose tissue contains thelargest pool of free cholesterol in the body, which performs a "buffer"function for circulating cholesterol. The efflux of excess free cholesterolto high-density lipoprotein (HDL) or its apolipoprotein is crucial formaintaining adipocyte cholesterol homeostasis. Liver X receptors (LXR)αand peroxisome proliferator-activated receptorγ(PPARγ) might play asignificant role in adipocytes cholesterol metabolism through mediationof cholesterol efflux.Increase evidence demonstrates that atherosclerosis is a chronicdisease. Inflammatory reaction and dyslipidemia play important rolesduring the initiation and progression of atherosclerosis. Previous studieshave demonstrated that monocyte chemoattractant protein-1 (MCP-1) andTNF-αis closely related to the severity of atherosclerosis. PPARγand its downstream targets, CD36, can be secreted by adipocyties and monocytes.Which are important nuclear transcription receptors and take modulatingeffects on inflammatory reaction and lipid metabolism.Niacin is a commonly used antidyslipidemic agent that favorablyaffects all lipids and lipoproteins, which has recently attracted renewedinterest, because it is currently the most potent drug available for thetreatment of low HDL-C and the only drug for lower levels oflipoproteins (a). Clinical trials demonstrated that niacin can significantlydecrease the incidence and mortality of CHD. The clinical benefits ofniacin appear to be beyond the cholesterol-lowering effects, suggestingthat niacin have pleiotropic effects on atherosclerosis. A major site of theaction of niacin is the adipose tissue. It has been indicated that niacinmediate their cardiovascular protective effects, at least in part, throughspecific favorable actions on adipocytes, which need to be further studied.ObjectiveThe aim of this study was to investigate the effect of niacin on serumleptin levels in hypercholesterolemic rabbits and the expression of leptin,PPARγ, and CD36 in adipocytes from hypercholesterolemic rabbits; toevaluate the effect of niacin on LXRαand PPARγexpression andHDL-induced cholesterol efflux in adipocytes from hypercholesterolemicrabbits. We also investigate the effects of niacin on the plaques formationof aorta and the plasma concentrations of MCP-1 and MCP-1 expressionin artery of hypercholesterolemic rabbits, further to elucisate the potentialmechanisms of niacin in anti-atherosclerogenetic role.MethodsTwelve rabbits fed with high-cholesterol diet for 8 weeks wererandomly divided into two groups: (1) high cholesterol group (n=6):maintained on high cholesterol diet for 6 weeks; (2) niacin group (n=6):the same cholesterol diet plus niacin (200mg·kg-1·d-1) for 6 weeks. Controlgroup (n=6) was fed with normal diet for 14 weeks. Subcutaneousadipose was collected from inguen for RNA analysis. Leptin and MCP-1levels in serum and adipocytes culture supernatant were measured byELISA. Reverse transcription polymerase chain reaction (RT-PCR) wasused to evaluate leptin, LXRα, PPARγand CD36 mRNA expressions in adipocytes and MCP-1 mRNA expression in aortas. Cholesterol effluxrate was determined through measuring release of radioactivity from3H-cholesterol prelabeled cells into medium containing HDL. The directeffects of niacin on leptin, LXRα, PPARγand CD36 expression wereassayed in primary rabbit adipocytes.Results1. After 8 weeks of high-cholesterol diet, plasma concentrations of TCand LDL-C were significantly increased (P＜0.001), plasmaconcentrations of TG and HDL-C was slightly increased. Niacintreatment for 6 weeks reduced plasma levels of TC and LDL-C ascompared with high-cholesterol group (P＜0.05). Plasma HDL-Cconcentrations of niacin group was increased (P＜0.05).2. Six weeks of treatment with niacin significantly decreased the serumleptin level and reduced leptin mRNA expression of subcutaneousadipose as compared with high cholesterol group. The reduction ofleptin mRNA expression of hypercholesterolemic rabbits by niacinwas negatively correlated with the upregulation of PPARγand CD36mRNA expression by niacin (r=-0.69, r=-0.63, respectively, P＜0.01).In vitro study, niacin dose-dependently inhibited leptin secretion andincreased CD36 and PPARγexpression in cultured adipocytes.3. Six weeks of niacin treatment significantly enhanced the cholesterolefflux from adipocytes, which was related to the increased mRNAexpression of LXRα(r=0.71, P＜0.05). In vitro study, niacindose-dependently stimulated LXRαand PPARγmRNA expression incultured adipocytes. And various doses of niacin-induced cholesterolefflux was positive correlation with LXRαand PPARγmRNAexpression (r=0.83 P＜0.01; r=0.76 P＜0.05; respectively).4. Administration with niacin significantly decreased the serum MCP-1level by 31.1% (P＜0.05) and suppressed MCP-1 mRNA expression ofsubcutaneous adipose by 24.1% (P＜0.05) as compared with that inhigh cholesterol group. The base concentrations of MCP-1 in thethree groups were very low. The levels of MCP-1 were significantlyincreased after 8 weeks of high cholesterol diet in starch group, andniacin administration significantly reduced the level of MCP-1 (156.5±21.7 pg/ml) as compared with high cholesterol group(227.1±23.0 pg/ml) at the end of the study. The concentration ofMCP-1 was positively associated with the plaques areas of aorta (r=0.71, P＜0.01).Conclusions1. Niacin administration can improve serum lipid. Niacin can reduceserum level and adipose mRNA expression of leptin, and upregulatePPARγand CD36 mRNA expression in hypercholesterolemic rabbits.2. LXRαand PPARγmight play a significant role in cholesterolefflux from adipocytes. Niacin administration can up-regulate LXRαandPPARγmRNA expression and promote the cholesterol efflux inadipocytes from hypercholesterolemic rabbits.3. Niacin administration can decreased the serum cholesterol, MCP-1concentrations and aorta MCP-1 mRNA expression, which may inhibit theformation of plaques of aortas in cholesterolemic rabbits.
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