Hypertriglyceridemia In Response Research Articles

Associations between Omega-3 Index increase and triacylglyceride decrease in subjects with hypertriglyceridemia in response to six month of EPA and DHA supplementation

IntroductionIngestion of long-chain n-3 PUFA effectively decreases serum triacylglycerol (TAG) levels and increases the Omega-3 Index, defined as the % of EPA and DHA in erythrocyte fatty acids. However, it remains unclear whether there is a relationship between the Omega-3 Index increase (ΔO3I increase) and the TAG level decrease (ΔTAG). We hypothesized that TAG reduction is strongly depended on Omega-3 Index increase. Subjects and methodsSecondary analyses of data from a former double-blind placebo-controlled trial in which 150 dyslipidemic statin-treated subjects were randomized to four capsules of fish oil daily either as re-esterified TAG or ethylesters in identical doses (1.01g EPA+0.67g DHA) or corn oil as a placebo for a period of six month. Results108 subjects fulfilled the criteria of the current study protocol and were included in the analyses. A weak but significant negative correlation between ΔO3I and ΔTAG was observed (r=−0.211, p<0.05). However, the relation between ΔO3I and serum ΔTAG was not linear (coefficients of determination R2: 0.044). After sub-grouping the study population into Omega-3 Index response groups, the group with a mean ΔO3I of>4% after six months of n-3 PUFA treatment demonstrated the greatest TAG reduction. Discussion and conclusionsA weak association between Omega-3 Index increase and TAG level decrease was found. This may be explained by highly fluctuating TAG levels, a large inter-individual difference in response of the Omega-3 Index, a cohort of subjects with only slightly elevated TAG levels and high Omega-3 Index values at baseline, and possibly to insufficient statistical power. Since there was no strong association between Omega-3 Index increase and the TAG level decrease, we conclude that changes in serum TAG levels are not a viable substitute for the Omega-3 Index to monitor treatment with EPA and DHA.

ATF4 Protein Deficiency Protects against High Fructose-induced Hypertriglyceridemia in Mice

Hypertriglyceridemia is the most common lipid disorder in obesity and type 2 diabetes. It results from increased production and/or decreased clearance of triglyceride-rich lipoproteins. To better understand the pathophysiology of hypertriglyceridemia, we studied hepatic regulation of triglyceride metabolism by the activating transcription factor 4 (ATF4), a member of the basic leucine zipper-containing protein subfamily. We determined the effect of ATF4 on hepatic lipid metabolism in Atf4(-/-) mice fed regular chow or provided with free access to fructose drinking water. ATF4 depletion preferentially attenuated hepatic lipogenesis without affecting hepatic triglyceride production and fatty acid oxidation. This effect prevented excessive fat accumulation in the liver of Atf4(-/-) mice, when compared with wild-type littermates. To gain insight into the underlying mechanism, we showed that ATF4 depletion resulted in a significant reduction in hepatic expression of peroxisome proliferator-activated receptor-γ, a nuclear receptor that acts to promote lipogenesis in the liver. This effect was accompanied by a significant reduction in hepatic expression of sterol regulatory element-binding protein 1c (SREBP-1c), acetyl-CoA carboxylase, and fatty-acid synthase, three key functions in the lipogenic pathway in Atf4(-/-) mice. Of particular significance, we found that Atf4(-/-) mice, as opposed to wild-type littermates, were protected against the development of steatosis and hypertriglyceridemia in response to high fructose feeding. These data demonstrate that ATF4 plays a critical role in regulating hepatic lipid metabolism in response to nutritional cues.

The ddY mouse: a model of postprandial hypertriglyceridemia in response to dietary fat

Postprandial hyperlipidemia (lipemia) is a risk factor for atherosclerosis. However, mouse models of postprandial hyperlipidemia have not been reported. Here, we report that ddY mice display marked postprandial hypertriglyceridemia in response to dietary fat. In ddY mice, the fasting serum total triacylglyceride (TG) concentration was 134 mg/dl, which increased to 571 mg/dl after an intragastric safflower oil load (0.4 ml/mouse). In C57BL/6J mice, these concentrations were 57 and 106 mg/dl, respectively. By lipoprotein analysis, ddY mice showed increases in chylomicron- and VLDL-sized TG fractions (remnants and VLDL) after fat load. In C57BL/6J mice, post-heparin plasma LPL activity after fat load was increased 4.8-fold relative to fasting. However, in ddY mice, the increase of LPL activity after fat load was very small (1.2-fold) and not significant. High fat feeding for 10 weeks led to obesity in ddY mice. A difference in LPL amino acid composition between C57BL/6J and ddY mice was detected but was deemed unlikely to cause hypertriglyceridemia because hypertriglyceridemia was not evident in other strains harboring the ddY-type LPL sequence. These findings indicate that postprandial hypertriglyceridemia in ddY mice is induced by decreased LPL activity after fat load and is associated with obesity induced by a high-fat diet.

Hyperlipidemic Guinea Pig Model: Mechanisms of Triglyceride Metabolism Disorder and Comparison to Rat

Guinea pigs and rats are both common animal models for hyperlipidemia studies. However, many recent studies have suggested that rats do not develop hypertriglyceridemia in response to cholesterol feeding. In the present work, the differences in triglyceride metabolism between guinea pigs and rats were investigated. Feeding a high-fat diet containing 0.1% cholesterol and 10% lard for 4 weeks led to a significant increase in plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and free fatty acid (FFA) in guinea pigs but not in rats. By contrast, hepatic TG levels in rats were greatly increased in response to the high-fat diet, while it remained unchanged in guinea pigs. Furthermore, the hepatic acyl CoA:diacylglycerol acyltransferase (DGAT) activity and microsomal triglyceride transfer protein (MTTP) mRNA levels in guinea pigs fed a high-fat diet were significantly higher than those in the control group, which implies an increased very-low-density lipoprotein (VLDL)-TG secretion rate in guinea pigs in response to a high-fat diet. Hepatic carnitine palmitoyltransferase-1 (CPT-1) activity and peroxisome proliferator-activated receptor-α (PPARα) mRNA levels were upregulated in guinea pigs, but not rats, fed a high-fat diet. These findings may explain the differences in plasma and hepatic TG concentrations between guinea pigs and rats. These results suggest that there are differences in triglyceride metabolism between the two species when fed high-fat diets.

Regulation of Hepatic ApoC3 Expression by PGC-1β Mediates Hypolipidemic Effect of Nicotinic Acid

Peroxisome proliferator-activated receptor (PPAR) γ coactivator-1β (PGC-1β) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1β is regulated by free fatty acids. Here we show that PGC-1β regulates plasma triglyceride metabolism through stimulating apolipoprotein C3 (APOC3) expression and elevating APOC3 levels in circulation. Remarkably, liver-specific knockdown of APOC3 significantly ameliorates PGC-1β-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1β and APOC3 is reduced in response to acute and chronic treatments with nicotinic acid, a widely prescribed drug for lowering plasma triglycerides. Adenoviral-mediated knockdown of PGC-1β or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1β transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRα and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1β as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects.

Biomarker correlates of survival in NSCLC: Role of RXRβ and PPARγ in mediating bexarotene impact on patient survival

7227 Background: Bexarotene is a selective modulator of retinoid X nuclear receptors (RXRs), which form heterodimers with many other nuclear receptors playing a critical role in cell growth, differentiation, and apoptosis. Loss of RXRs is seen in many advanced tumors, including NSCLC and higher RXR levels in NSCLC lung biopsies (stages I-III) have been correlated with longer overall survival. Two large first line NSCLC Phase III trials reported at ASCO 2005 (SPIRIT I and II) showed that while no benefit in overall survival was seen adding bexarotene to two chemo regimens, a large (36%) subpopulation of patients in both trials that had high grade hypertriglyceridemia in response to bexarotene had significantly longer survival. A retrospective analysis was conducted to evaluate the baseline characteristics of these patients and to examine the level of expression of RXR and one of its partners (PPARγ) in lung tumor tissue biopsies obtained from a subgroup of patients in both studies. Methods: RXRs (α,β,γ) and PPARγ expression levels in lung tumor tissue from patients in SPIRIT I and II trials (stage IIIB/IV) taken prior to study entry were assessed by Q-PCR analysis of RNA isolated from microdissected lung tumor tissue biopsies. Cox regression and Kaplan-Meier survival estimation were used for statistical evaluations. Results: In an initial subset of 41 patients, RXRβ expression in lung tumor showed positive correlation with survival. High RXRβ = longer survival (median survival 438 days), low RXR shorter (MS = 317). Treatment with bexarotene increased the differences (RXRβ Hi, MS = 627 days; RXRβ low = 211 days). PPARγ showed a negative correlation with survival and those patients with RXRβ Hi/PPARγ low ratios had the longest MS (627 days vs. 226 days for the RXRβ low/PPARγ high group), a difference that was magnified by bexarotene treatment. Conclusions: RXRβ expression level correlates with a positive survival in late stage NSCLC while PPARγ shows negative correlation. Bexarotene treatment enhances the survival differences, supporting an involvement of triglyceride and lipid metabolism as regulated by these two key nuclear receptors in the longer survival seen in the 215 patients in the high triglyceride subgroup. [Table: see text]

Sugars, hypertriglyceridemia, and cardiovascular disease

Short-term studies consistently show that raising the carbohydrate content of the diet increases serum triacylglycerol concentrations. As compared with starches, sugars (particularly sucrose and fructose) tend to increase serum triacylglycerol concentrations by approximately 60%. The magnitude of the effect depends on other aspects of the diet, including the total amount of carbohydrate and the types of fat, carbohydrate, and fiber, but definitive studies to describe the dose-response relations are not available. Longer-term studies show that some high-carbohydrate diets are not associated with increased fasting serum triacylgycerol concentrations. However, sedentary subjects with upper-body and visceral obesity who have the metabolic syndrome tend to be at higher risk for hypertriglyceridemia in response to high-sucrose and high-carbohydrate diets; moderate weight loss mitigates the effect. Hyperinsulinemia or insulin resistance may play a role in promoting higher rates of VLDL synthesis and hypertriglyceridemia in obesity, but the mechanisms remain unclear. The effect of fructose in promoting triacylglycerol synthesis is independent of insulinemia, however. In terms of the long-term effects of diets high in sugars on the risk of cardiovascular disease, available epidemiologic evidence indicates no association of sugars or total carbohydrate intake per se, but high dietary glycemic load is associated with higher serum triacylglycerol concentrations and greater risk of coronary heart disease in women. Studies are needed to delineate the independent effects of dietary sugars and glycemic load on serum triacylglycerol concentrations in lean and obese men and women and to determine whether the elevations in fasting and fed concentrations of serum triacylglycerol with high-carbohydrate and high-sugars diets are associated with increased risk of cardiovascular disease.

Effect of dietary cholesterol and alloxan-diabetes on tissue cholesterol and apolipoprotein E mRNA levels in the rabbit

Alloxan-diabetic rabbits develop hypercholesterolemia and hypertriglyceridemia in response to cholesterol feeding. To determine whether alterations in apolipoprotein composition of plasma lipoproteins were due to changes in apolipoprotein gene expression, we measured the steady state apoE mRNA levels in several tissues from both control and diabetic rabbits. Control rabbits were fed either chow or chow plus 1.5% cholesterol (chow-fed or cholesterol-fed groups) and diabetic rabbits were fed either chow or chow plus 0.5% cholesterol for dietary periods of 5, 21, and 42 days. The tissues examined were liver, small intestine, brain, adrenals, and aorta. ApoE mRNA levels were measured by Northern and dot blot analysis with a human apoE cDNA probe. In control rabbits fed either chow or cholesterol diets for up to 42 days, the steady state apoE mRNA levels remained relatively constant in all of the tissues examined. In contrast, in alloxan-diabetic rabbits fed a 0.5% cholesterol diet, apoE mRNA was reduced in liver, brain, and adrenals (46 +/- 19%, 56 +/- 5%, and 39 +/- 18% of chow-fed control, respectively), but showed little change in the aorta (91 +/- 22% of chow-fed control). Despite a similar increase in plasma cholesterol, the cholesterol content of the liver and adrenals of cholesterol-fed diabetic rabbits were 20% and 50%, respectively, of that of the liver and adrenals in cholesterol-fed control rabbits. The result that apoE mRNA levels and tissue cholesterol content are altered in the diabetic cholesterol-fed rabbit suggests that insulin deficiency in the rabbit may influence apoE gene expression and tissue cholesterol homeostasis.

Relationship of an abnormal plasma lipoprotein to protection from atherosclerosis in the cholesterol-fed diabetic rabbit.

Alloxan-diabetic rabbits develop a pronounced hypercholesterolemia and hypertriglyceridemia in response to cholesterol feeding. Despite higher levels of plasma cholesterol, these animals have much less atherosclerosis than cholesterol-fed nondiabetics. To determine whether this effect is due to properties of the lipoproteins, we compared chemical, physical, and metabolic characteristics of a very low density lipoprotein (VLDL) fraction (d less than 1.019 g/ml) from the diabetic and nondiabetic cholesterol-fed rabbits. The molar ratio of triglyceride to cholesteryl ester in the particles from diabetic animals ranged from 2:1 to 6:1, and this ratio remained constant in subfractions from individual rabbits. Triglyceride from nondiabetic control animals was a minor component. Differential scanning calorimetry showed a distinct order-disorder phase transition for cholesteryl ester at approximately 42 degrees C in the fractions from control animals, whereas in fractions from most of the diabetics no such transition was observed, indicating that both triglyceride and cholesteryl ester are present in the core of the same particle. The relative amount of apoprotein E in particles from diabetic animals was much less than that of cholesterol-fed controls. The ability of the lipoproteins from both groups to stimulate cholesteryl ester formation in mouse peritoneal macrophages also was tested. Lipoproteins from cholesterol-fed controls stimulated cholesteryl ester formation in a dose-dependent manner, but particles from the diabetic group had little or no effect. The results suggest that the presence of unusual VLDL particles in diabetic cholesterol-fed rabbits is responsible, at least in part, for the reduced incidence of atherosclerosis in this animal model.

Effects of methylprednisolone on plasma lipids and aortic mucopolysacchasrides of normal and cholesterol-fed rabbits.

SummaryMethylprednisolone (Medrol) was administered to normal and cholesterolfed rabbits for a period of 2 months, and its effects upon plasma cholesterol and triglyceride concentrations and upon the content of aortic acid mucopolysaccharides (AMPS) were studied. Rabbits fed a chow diet developed both a hypercholesterolemia and a hypertriglyceridemia in response to Medrol, and the already elevated cholesterol and triglyceride levels induced by cholesterol feeding were further elevated by Medrol. Despite the hyperlipemia, none of the Medrol-treated animals developed aortic atherosclerosis. Medrol had no significant effect upon the total aortic AMPS content in control animals but it did alter the aortic AMPS content and pattern of cholesterol-fed rabbits. The most significant effect was an increase in an AMPS of low sulfate content. Since all animals fed cholesterol developed some degree of pulmonary atherosclerosis, it is postulated that the antiatherogenic action of the hormone on the aorta is more closel...