Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster

We investigated whether intestinal lipoprotein overproduction in a fructose-fed, insulin-resistant hamster model is prevented with insulin sensitization. Syrian Golden hamsters were fed either chow, 60% fructose for 5 wk, chow for 5 wk with the insulin sensitizer rosiglitazone added for the last 3 wk, or 60% fructose plus rosiglitazone. In vivo Triton studies showed a 2- to 3-fold increase in the large (Svedberg unit > 400) and smaller (Sf 100-400) triglyceride-rich lipoprotein particle apolipoprotein B48 (apoB48) but not triglyceride secretion with fructose feeding in the fasted state (P < 0.01) and partial normalization with rosiglitazone in fructose-fed hamsters. Ex vivo pulse-chase labeling of enterocytes confirmed the oversecretion of apoB48 lipoproteins with fructose feeding. Intestinal lipoprotein oversecretion was associated with increased expression of microsomal triglyceride transfer protein expression. With rosiglitazone treatment of fructose-fed hamsters, there was approximately 50% reduction in apoB48 secretion from primary cultured enterocytes and amelioration of the elevated microsomal triglyceride transfer protein mass and activity in fructose-fed hamsters. In contrast, in the postprandial state, the major differences between nutritional and drug intervention protocols were evident in triglyceride-rich lipoprotein triglyceride and not apoB48 secretion rates. The data suggest that intestinal lipoprotein overproduction can be ameliorated with the insulin sensitizer rosiglitazone.     

Intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids in the fasting state: studies in insulin-resistant and insulin-sensitized Syrian golden hamsters

It is not known whether intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids (FFA). We examined the effect of an intralipid and heparin infusion on the intestinal lipoprotein production rate (PR) in insulin-sensitive [chow-fed (CHOW)], insulin-resistant [60% fructose (FRUC) or 60% fat-fed (FAT)], and insulin-sensitized [FRUC or FAT plus rosiglitazone (RSG)-treated] Syrian Golden hamsters. After 5 wk of treatment, overnight-fasted hamsters underwent in vivo Triton WR-1339 studies for measurement of apolipoprotein B48 (apoB48) PR in large (Svedberg unit, >400) and small (Svedberg unit, 100-400) lipoprotein fractions, with an antecedent 90-min infusion of 20% intralipid and heparin (IH) to raise plasma FFA levels approximately 5- to 8-fold vs. those in the saline control study. IH markedly increased apoB48 PR in CHOW by 3- to 5-fold, which was confirmed ex vivo in pulse-chase experiments in primary cultured hamster enterocytes. Oleate, but not glycerol, infusion was associated with a similar elevation of apoB48 PR as IH. In FRUC and FAT, basal (saline control) apoB48 PR was approximately 4-fold greater than that in CHOW; there was no additional stimulation with IH in vivo and only minimal additional stimulation ex vivo. RSG partially normalized basal apoB48 PR in FAT and FRUC, and PR was markedly stimulated with IH. We conclude that intestinal lipoprotein production is markedly stimulated by an acute elevation of plasma FFAs in insulin-sensitive hamsters, in which basal production is low, but minimally in insulin-resistant hamsters, in which basal production is already elevated. With RSG treatment, basal PR is partially normalized, and they become more susceptible to the acute FFA stimulatory effect.     

Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity

Insulin resistance is strongly associated with metabolic dyslipidemia, which is largely a postprandial phenomenon. Though previously regarded as a consequence of delayed triglyceride-rich lipoprotein clearance, emerging evidence present intestinal overproduction of apoB-48-containing lipoproteins as a major contributor to postprandial dyslipidemia. The majority of mechanistic information is however derived from animal models, namely the fructose-fed Syrian Golden hamster, and extension to human studies to date has been limited. Work in our laboratory has established that aberrant insulin signalling exists in the enterocyte, and that inflammation appears to induce intestinal insulin resistance. The intestine is a major site of lipid synthesis in the body, and upregulated intestinal de novo lipogenesis and cholesterogenesis have been noted in insulin resistant and diabetic states. There is also enhanced dietary lipid absorption attributable to changes in ABCG5/8, NPC1L1, CD36/FAT, and FATP4. Proteins that are involved in chylomicron assembly and secretion, including MTP, MGAT, DGAT, apoAI-V, and Sar1 GTPase, show evidence of increased expression and activity levels. Increased circulating free fatty acids, typically observed in insulin resistant states, may serve to deliver lipid substrates to the intestine for enhanced chylomicron assembly and secretion. To compound the dysregulation of intestinal lipid metabolism, there are changes in the secretion of gut-derived peptides, which include GLP-1, GLP-2, and GIP. Thus, accumulating evidence presents intestinal lipoprotein secretion as a highly regulated process that is sensitive to perturbations in whole body energy homeostasis, and is severely perturbed in insulin resistant states.     

Treatment with atorvastatin ameliorates hepatic very-low-density lipoprotein overproduction in an animal model of insulin resistance, the fructose-fed Syrian golden hamster: evidence that reduced hypertriglyceridemia is accompanied by improved hepatic insulin sensitivity

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster has been previously documented to exhibit considerable hepatic very-low-density lipoprotein (VLDL) overproduction concomitant with the development of whole body insulin resistance. Here, we investigated whether hepatic lipoprotein overproduction can be ameliorated by treatment with a hydroxymethyl glutaryl conenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, using a series of ex vivo experiments. Hamsters were fed a fructose-enriched diet for 14 days to induce a state of insulin resistance, and then continued on a fructose-enriched diet supplemented with or without 40 mg/kg atorvastatin per day for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride levels. There was a significant decline in plasma triglyceride levels following supplementation with the inhibitor (50% to 59%; P <.05). Experiments with primary hepatocytes revealed a decreased VLDL-apolipoprotein B (apoB) production (37.4% +/- 10.4%; P <.05) in hamsters treated with atorvastatin. Interestingly, atorvastatin treatment partially attenuated (by 23%) the elevated hepatic level of microsomal triglyceride transfer protein (MTP) induced by fructose feeding. There was molecular evidence of improved hepatic insulin sensitivity with atorvastatin treatment based on assessment of the phosphorylation status of the insulin receptor and the expression of protein tyrosine phosphatase-1B. The improvement in insulin signaling was not mediated by a change in hepatic triglyceride accumulation as no significant difference was observed in liver triglyceride levels. Taken together, these data suggest that statins can ameliorate the VLDL-apoB overproduction state observed in a fructose-fed, insulin-resistant hamster model, and may potentially contribute to an enhanced hepatic insulin sensitivity.     

Mechanism of intestinal lipoprotein overproduction in insulin resistant humans

Triglyceride-rich lipoproteins (TRLs) derived from the intestine are increased in insulin resistant states both in the post-prandial and fasted state and are associated with increased cardiovascular risk. Impaired clearance has long been invoked to explain this accumulation of intestinal TRLs, but more recent studies have highlighted the fact that the production rate of apolipoprotein (apo) B-48-containing particles is also increased in insulin resistance and Type 2 diabetes. Recent data also indicate that the enterocyte, similar to the hepatocyte, overproduces lipoprotein particles in response to an elevation of plasma free fatty acids. It is not yet clear precisely how much this overproduction of intestinal lipoprotein particles contributes to the hypertriglyceridemia of insulin resistant states. We speculate that chronic intestinal overproduction of apoB-48 primes the intestine to rapidly and efficiently facilitate the absorption of ingested fat, enhancing the assembly and secretion of intestinal TRL, and hence contributing to post-prandial lipemia.     

Intestinal assembly and secretion of highly dense/lipid-poor apolipoprotein B48-containing lipoprotein particles in the fasting state: evidence for induction by insulin resistance and exogenous fatty acids

Emerging evidence suggests that overproduction of intestinally derived apolipoprotein (apo) B48-containing lipoprotein particles may be an important contributor to both fasting and postprandial dyslipidemia in insulin-resistant states. Mechanisms regulating the assembly and secretion of apoB48-containing lipoproteins are not fully understood particularly in the diabetic/insulin-resistant intestine. In the present study, we have investigated the density profile of apoB48 lipoproteins assembled in primary hamster enterocytes. Both intracellular and secreted apoB48 particles were examined in intestinal enterocytes isolated from normal or insulin-resistant fructose-fed hamsters, as well as in enterocytes treated with exogenous oleic acid. Microsomal luminal contents and culture media were analyzed by discontinuous and sequential ultracentrifugation on sucrose and KBr gradients, respectively. ApoB48 was mostly secreted on VLDL-, LDL-, and denser HDL-sized particles in the fasting state. In pulse-chase labeling experiments, nascent apoB48-containing particles initially accumulated in the microsomal lumen as HDL-sized particles, with subsequent formation of apoB48-VLDL particles, with only a minute amount of chylomicrons observed. Treatment with 720 mu mol/L of oleic acid, increased microsomal apoB48 HDL synthesis, and induced a marked shift toward lighter more buoyant particles. A marked enhancement in assembly of apoB48-containing lipoproteins was also observed in the microsomal lumen of fructose-fed hamster enterocytes, suggesting facilitated assembly and secretion of dense intestinal lipoprotein particles in insulin-resistant states. Overall, these observations suggest that a major proportion of apoB48-containing lipoprotein particles is assembled and secreted as highly dense, HDL-sized particles. The production of these small, dense, and potentially atherogenic apoB48 particles can be stimulated by increased free fatty acid flux as well as in insulin-resistant diabetes.     

高脂饲养大鼠脂肪组织抵抗素、脂联素及其受体的表达

目的阐明抵抗素、脂联素及其受体在胰岛素抵抗发生中的作用。方法30只Wistar雄性大鼠随机分为对照组和高脂组。用逆转录聚合酶链反应和Southem blot方法分析抵抗素、脂联素和脂联素受体表达的改变。结果高脂组大鼠体重明显增加，空腹血糖、低密度脂蛋白胆固醇、总游离脂肪酸、胰岛素和HOMA胰岛素抵抗指数明显高于对照组，高密度脂蛋白胆固醇明显低于对照组，糖耐量和胰岛素耐量明显下降（P均〈0．01）。高脂组脂肪组织抵抗素和脂联素的表达均明显下降（P〈0．01）；脂联素受体1的表达呈下降趋势，但与对照组相比无统计学意义（P〉0．05）。结论抵抗素和脂联素表达的下降在高脂饮食导致的胰岛素抵抗的发生中起着重要作用，脂联素受体1水平的降低可能是脂联素敏感性降低的重要原因之一。     

Insulin regulates hepatic apolipoprotein B production independent of the mass or activity of Akt1/PKBalpha

Insulin is known to be a downregulator of apolipoprotein B (apoB) via the phosphatidylinositol 3-kinase (PI3K) pathway. Akt, also known as protein kinase B (PKB), is a serine/threonine kinase downstream target of PI3K. Recent studies in the fructose-fed hamster model of insulin resistance have shown that hepatic very-low-density lipoprotein (VLDL) secretion is associated with reduced phosphorylation of Akt, suggesting a potential link between Akt expression and/or activity and apoB production in hepatocytes. We hypothesized that overexpression of Akt1 downregulates apoB production. An expression vector with a constitutively active form of Akt1 was transfected in the rat hepatoma McArdle cells (McA RH-7777), McA cells stably expressing human apoB-15 and apoB-48 (15% and 48% of total apoB length), and human hepatoma HepG2. The overexpressed Akt1 was phosphorylated at Ser473 independent of acute insulin stimulation, suggesting that it was catalytically active. Despite dosage-dependent overexpression of Akt1 in both McA and HepG2 cells, neither intracellular nor secreted protein mass of intact apoB or transfected human apoB-15/apoB-48 was significantly affected by high intracellular levels of Akt1. Radiolabeling experiments also yielded no difference in the amount of newly synthesized apoB when comparing transfected and mock-transfected cells. Transfection in conjunction with high-dose insulin did not significantly decrease the secretion of either apoB-100 or apoB-48 in McA cells, or apoB-100 in HepG2 cells. HepG2 cells were more sensitive to the inhibitory effects of insulin on apoB secretion compared to McA cells, but neither model responded to Akt1. Overall, the data suggest that acute insulin-mediated inhibition of apoB may not be mediated by Akt1 and that insulin signaling molecules upstream of Akt1 may be more important in mediating control of apoB secretion.     

Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the efficacy and mechanisms of action of rosuvastatin, a HMG-CoA reductase inhibitor, in ameliorating metabolic dyslipidemia in insulin-resistant states. Fructose feeding for a 2-week period induced insulin resistance and a significant increase in hepatic secretion of VLDL. This was followed by a fructose-enriched diet with or without 10 mg/kg rosuvastatin for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups (n=6, p<0.001). However, there was a significant decline (30%, n=8, p<0.05) in plasma triglyceride levels following rosuvastatin feeding (10 mg/kg). A significant decrease (n=6, p<0.05) was also observed in VLDL-apoB production in hepatocytes isolated from drug-treated hamsters, together with an increased apoB degradation (n=6, p<0.05). Similar results were obtained in parallel cell culture experiments in which primary hepatocytes were first isolated from chow-fed hamsters, and then treated in vitro with 15 microM rosuvastatin for 18 h. Rosuvastatin at 5 microM caused a substantial reduction in synthesis of unesterified cholesterol and cholesterol ester (98 and 25%, n=9, p<0.01 or p<0.05) and secretion of newly synthesized unesterified cholesterol, cholesterol ester, and triglyceride (95, 42, and 60% reduction, respectively, n=9, p<0.01 or p<0.05). This concentration of rosuvastatin also caused a significant reduction (75% decrease, n=4, p<0.01) in the extracellular secretion of VLDL-apoB100, accompanied by a significant increase in the intracellular degradation of apoB100. There was a 12% reduction (not significant, p>0.05) in hepatic MTP and no changes in ER-60 (a chaperone involved in apoB degradation) protein levels. Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by rosuvastatin in a process involving enhanced apoB degradation. This appears to lead to a significant amelioration of hepatic VLDL-apoB overproduction observed in the fructose-fed, insulin-resistant hamster model.     

The effect of metformin and rosiglitazone on postprandial lipid metabolism in obese insulin-resistant subjects

INTRODUCTION: Obese insulin-resistant individuals exhibit a dyslipidaemia due to raised levels of both hepatically and intestinally derived lipoproteins. However, little is known about the related dysregulation of intestinally derived lipoproteins. We examined whether the insulin-sensitizing agents, metformin and rosiglitazone, improve intestinal lipoprotein metabolism in obese insulin-resistant individuals. METHODS: Thirty male obese (body mass index > 26; waist circumference > 100 cm) insulin-resistant [homeostasis model assessment (HOMA) score > 2.0] subjects were randomized to either a metformin (1 g bd), rosiglitazone (4 mg bd) or control treatment group for a period of 8 weeks. Fasting and postprandial lipid metabolism was studied before and after the intervention period. RESULTS: Metformin and rosiglitazone both significantly improved insulin sensitivity, but this was not paralleled by improvement in dyslipidaemia. With rosiglitazone relative to control there was a significant (p < 0.05) increase in the area under the apolipoprotein (apo) B48 curve following the oral fat load and a decrease in the ratio of triglyceride to apo B48 levels postprandially following rosiglitazone treatment. CONCLUSION: In obese insulin-resistant subjects metformin and rosiglitazone both improve insulin sensitivity, as measured by HOMA, without improvement in lipid metabolism. Rosiglitazone may have a detrimental effect on chylomicron metabolism by an increase in postprandial apo B48 levels, and this requires further investigation.     

Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age- and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.     

Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats.

Thiazolidinediones (TZDs), a class of antidiabetic agents, are specific agonists of peroxisome proliferator activator receptor (PPARgamma). However, their mechanisms of action, and the in vivo target tissues that mediate insulin sensitization are not well understood. The aim of this study was to investigate the role of glucose transporters (GLUT-1 and GLUT-4) in the TZD insulin-sensitizer action. The effects of rosiglitazone treatment were studied using Zucker (fa/fa) rats after 7 days of oral dosing (3.6 mg/kg/d). Rosiglitazone lowered (approximate 80%) basal plasma insulin levels in obese rats and substantially corrected (approximately 50%) insulin resistance based upon results from hyperinsulinemic euglycemic clamp studies. GLUT-4 protein levels were reduced (approximately 75%) in adipose tissue of obese rats and treatment with rosiglitazone normalized them. Interestingly, GLUT-1 protein content was increased in adipose tissue ( thick approximate 150%) and skeletal muscle (approximately 50%) of obese rats and treatment with rosiglitazone increased it even more by 5.5-fold in fat and by 2.5-fold in muscle. Consistent with these results, basal (GLUT-1-mediated) transport rate of 3-O-methyl-D-glucose into isolated epitrochlearis muscle was elevated in response to rosiglitazone. Incubation of fully differentiated 3T3-L1 adipocytes with the drug for 7 days increased the levels of GLUT-1 protein, but did not affect GLUT-4 levels. In conclusion, rosiglitazone may improve insulin resistance in vivo by normalizing GLUT-4 protein content in adipose tissue and increasing GLUT-1 in skeletal muscle and fat. While the drug has a direct effect on GLUT-1 protein expression in vitro without a direct effect on GLUT-4 suggests that direct and indirect effects of rosiglitazone on glucose transporters may have an important role in improving insulin resistance in vivo.     

极低密度脂蛋白与胰岛素抵抗患者的脂代谢紊乱

极低密度脂蛋白(VLDL)是机体转运内源性甘油三酯的主要形式,可分为大颗粒的VLDL1和小颗粒的VLDL2。VLDL血浓度升高是胰岛素抵抗(IR)脂代谢紊乱的主要特征,以VLDL1升高为主。其升高的机制与IR密切相关,包括:磷脂酰肌醇3激酶信号转导途径受损,固醇调节元件结合蛋白-C表达上调,游离脂肪酸大量内流,载脂蛋白(apo)B-100稳定性增加、肠内apoB-48水平升高,脂蛋白脂酶活性下降及低密度脂蛋白受体清除途径受损,导致VLDL生成过度、清除减弱,从而使其血浓度升高。     

Depot-specific regulation of perilipin by rosiglitazone in a diabetic animal model

Treatment with rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR) gamma agonist, results in lipid storage coupled with reduced release of free fatty acids into the circulation. Many studies have reported that PPAR-gamma agonists increase subcutaneous adiposity but have no effect on visceral fat mass. Perilipin, a family of phosphoproteins that coat intracellular lipid droplets in adipocytes, is essential for enlargement of lipid droplets. Recently, a functional PPAR-responsive element was identified within the murine perilipin gene. We hypothesized that the depot-specific regulation of perilipin by rosiglitazone may be associated with the fat-redistribution and insulin-sensitizing effects of rosiglitazone. After 6 weeks of rosiglitazone treatment in Otusuka Long-Evans Tokushima Fatty rats, an animal model of type 2 diabetes mellitus, we measured changes in adiposity, triglyceride content in liver and muscle, morphology of the pancreas, and perilipin messenger RNA and protein expression in adipose tissue. Rosiglitazone increased subcutaneous adiposity, decreased triglyceride content of liver and muscle, decreased plasma free fatty acids (2107 +/- 507 micromol/L in the placebo group vs 824 +/- 148 micromol/L in the rosiglitazone group; P < .05), and improved insulin resistance. The islets of placebo-treated rats showed hypertrophy and destruction, whereas the islets of rosiglitazone-treated rats showed hypertrophy, but the islet architecture remained intact. Perilipin messenger RNA and protein expression increased in subcutaneous fat, but did not change in visceral fat, after rosiglitazone treatment. In 3T3-L1 cells, rosiglitazone pretreatment decreased lipolysis and increased perilipin protein. In conclusion, increased perilipin expression in subcutaneous fat after rosiglitazone treatment is likely to be a mediator of reduced lipolysis, resulting in lipid storage in subcutaneous fat, fat redistribution, and insulin sensitization.     

Evaluation of anti-atherosclerotic activities of PPAR-α, PPAR-γ, and LXR agonists in hyperlipidemic atherosclerosis-susceptible F(1)B hamsters

BackgroundFenofibrate, a PPAR-α agonist and rosiglitazone, a PPAR-γ agonist, reduce triglycerides and fatty acids in humans and in animal disease models. The efficacy of PPAR-α agonists in mouse model of human atherosclerosis disease has shown mixed results, and efficacy of PPAR-γ and liver X receptor (LXR) agonists has not been evaluated in cholesterol ester transfer protein (CETP) producing animal models.Methods and resultsThe efficacy of PPAR-α, PPAR-γ and LXR agonists on lipid lowering and antiatherosclerotic activities was studied in atherosclerosis-susceptible F₁B hamster that showed greater responsiveness to dietary fat and cholesterol (HFHC) diet and increased severity of atherosclerosis compared to Golden Syrian (GS) hamsters (aortic lesion 0.3% in GS vs 5% in F₁B). F₁B hamsters were fed HFHC diet and simultaneously treated with fenofibrate, rosiglitazone, and T0901317 (a pan LXR agonist) for 8 weeks. Fenofibrate lowered triglycerides and LDL-C by >80%, rosiglitazone did not significantly impact plasma lipid levels, and as expected, T0901317 increased triglycerides by 3-fold and HDL-C by 50%. The lesions in the aortic arch area as measured by en face method, decreased by 81%, 38% and 35%, following fenofibrate, rosiglitazone, and T0901317 treatments, respectively. In F₁B hamster regression model, fenofibrate decreased levels of triglycerides and LDL-C by >85%, and LDL-C by >70%, respectively, which resulted in ～50% regression of aortic lesions compared to vehicle treated group, and ～36% compared to baseline.ConclusionsThese results demonstrate that: (a) F₁B hamster is more sensitive to developing diet-induced hyperlipidemia and atherosclerosis; and (b) the greater antiatherosclerotic efficacy of fenofibrate occurred primarily via reductions in proatherogenic lipoproteins. Thus, PPAR-α selective agonist shows a greater anti-atherosclerotic response compared to PPAR-γ and LXR agonists in diet-induced atherosclerosis-susceptible F₁B hamster.     

Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance

An important complication of insulin-resistant states, such as obesity and type 2 diabetes, is an atherogenic dyslipidemia profile characterized by hypertriglyceridemia, low plasma high-density lipoproteins (HDL) cholesterol and a small, dense low-density lipoprotein (LDL) particle profile. The physiological basis of this metabolic dyslipidemia appears to be hepatic overproduction of apoB-containing very low-density lipoprotein (VLDL) particles. This has focused attention on the mechanisms that regulate VLDL secretion in insulin-resistant states. Recent studies in animal models of insulin resistance, particularly the fructose-fed hamster, have enhanced our understanding of these mechanisms, and certain key factors have recently been identified that play important roles in hepatic insulin resistance and dysregulation of the VLDL secretory process. This review focuses on these recent developments as well as on the hypothesis that an interaction between enhanced flux of free fatty acids from peripheral tissues to liver, chronic up-regulation of de novo lipogenesis by hyperinsulinemia and attenuated insulin signaling in the liver may be critical to the VLDL overproduction state observed in insulin resistance. It should be noted that the focus of this review is on molecular mechanisms of the hypertriglyceridemic state associated with insulin resistance and not that observed in association with insulin deficiency (e.g., in streptozotocin-treated animals), which appears to have a different etiology and is related to a catabolic defect rather than secretory overproduction of triglyceride-rich lipoproteins.     

n-3多不饱和脂肪酸对高脂诱导胰岛素抵抗大鼠肝脏和骨骼肌胰岛素受体及葡萄糖转运蛋白4的作用

目的探讨n-3脂肪酸对饱和脂肪酸诱导的大鼠胰岛素抵抗(IR)肝脏和骨骼肌胰岛素受体(InsR)及葡萄糖转运蛋白4(GluT-4)的作用。方法45只雄性Wistar大鼠分为对照组、高脂组和n-3脂肪酸组。各组饲养11周后测定有关指标。结果(1)与对照组比较，高脂组大鼠体内脂肪相对含量、空腹血糖(FBG)、血清胰岛素(Ins)、甘油三酯(TG)、胆固醇(TC)、胰岛素抵抗指数(IRI)、肝脏TC和TG含量、肌肉中TG含量均显著升高；而肌肉组织中TC含量无显著改变，高脂组肝脏和肌肉InsR含量、肌肉Glut-4蛋白的相对含量均明显下降。(2)n-3脂肪酸组体内脂肪相对含量、FBG、Ins、TG、TC、IRI、肝脏TC和TG含量、肌肉组织中TG含量较高脂组均明显降低，肝脏InsR含量和肌肉GluT-4较高脂组明显升高。结论适量n-3脂肪酸代替饱和脂肪酸的一部分热量后，可增加IR大鼠肝脏InsR含量和肌肉GluT-4蛋白表达。     

A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis

We have cloned a human macrophage receptor that binds to apolipoprotein (apo)B48 of dietary triglyceride (TG)-rich lipoproteins. TG-rich lipoprotein uptake by the apoB48R rapidly converts macrophages and apoB48R-transfected Chinese hamster ovary cells in vitro into lipid-filled foam cells, as seen in atherosclerotic lesions. The apoB48R cDNA (3,744 bp) encodes a protein with no known homologs. Its approximately 3.8-kb mRNA is expressed primarily by reticuloendothelial cells: monocytes, macrophages, and endothelial cells. Immunohistochemistry shows the apoB48R is in human atherosclerotic lesion foam cells. Normally, the apoB48R may provide essential lipids to reticuloendothelial cells. If overwhelmed, foam cell formation, endothelial dysfunction, and atherothrombogenesis may ensue, a mechanism for cardiovascular disease risk of elevated TG.