Cholesteryl ester transfer protein expression is down-regulated in hyperinsulinemic transgenic mice

Berti, Jairo Augusto; Casquero, A.C.; Patricio, Patricia; Bighetti, E.J.B.; Carneiro, Everardo M.; Boschero, Antônio Carlos; Oliveira, Helena Coutinho Franco de

doi:10.1194/jlr.m300036-jlr200

Cited by 11 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During the treatment, mice had free access to sugar cubes and 5% glucose in the drinking water to prevent hypoglycemia. As reported previously for mice under this protocol (28), carbohydrate supplementation (CARB) led to a significant reduction in chow consumption and to increased water consumption that was independent of the insulin treatment (Table 2). At the time of sacrifice, mean plasma insulin levels were significantly increased by 135% in the INS ϩ CARB group when compared with the untreated animals ( Table 3).…”

Section: Acute and Chronic Insulin Stimulations Down-regulate Ucp3 Atsupporting

confidence: 76%

“…Control groups included saline-injected mice and mice treated with the antilipolytic agent nicotinic acid (75 mg/kg body weight; Sigma-Aldrich). The effects of chronic hyperinsulinemia were investigated using subcutaneous injections of increasing doses of neutral protamine Hagedorn insulin (0.14 -1.68 units/day; Novolin N, Novo Nordisk) for 15 days (28,29). Two-thirds of the dose was given at 2000 h and one-third at 0800 h. To prevent hypoglycemia, the rodent chow diet was supplemented with sugar cubes, and 5% (w/v) glucose was added to the drinking water (INS ϩ CARB).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart

Harmancey

Haight

Watts

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

The risk for heart failure and death after myocardial infarction is abnormally high in diabetic subjects. We and others have shown previously that mitochondrial uncoupling protein 3 (UCP3) improves functional recovery of the rodent heart during reperfusion. Here, we demonstrate that pharmacological induction of hyperinsulinemia in mice down-regulates myocardial UCP3. Decreased UCP3 expression was linked to the development of selective insulin resistance in the heart, characterized by decreased basal activity of Akt but preserved activity of the p44/42 mitogen-activated protein kinase, and overactivation of the sterol regulatory element-binding protein (SREBP)-1-mediated lipogenic program. In cultured myocytes, insulin treatment and SREBP-1 overexpression decreased, whereas SREBP-1 interference increased, peroxisome proliferator-activated receptor-stimulated expression of UCP3. Promoter deletion and site-directed mutagenesis identified three functional sterol regulatory elements in the vicinity of a known complex intronic enhancer. Increased binding of SREBP-1 to this DNA region was confirmed in the heart of hyperinsulinemic mice. In conclusion, we describe a hitherto unknown regulatory mechanism by which insulin inhibits cardiac UCP3 expression through activation of the lipogenic factor SREBP-1. Sustained down-regulation of cardiac UCP3 by hyperinsulinemia may partly explain the poor prognosis of type 2 diabetic patients after myocardial infarction.Type 2 diabetes represents 95% of all diabetes cases, and its incidence is expected to soar in the next decades as a consequence of the obesity epidemic (1). The insulin resistance and hyperinsulinemia that characterize this category of patients are both strong predictors of ischemic heart disease (2, 3). In addition to increasing the incidence of myocardial infarction, diabetes is also associated with increased cardiac morbidity and mortality following revascularization interventions (4 -7). Following pharmacological and surgical revascularization techniques, type 2 diabetic patients treated with insulin have more postoperative complications and have a mortality rate 2-3-fold higher than type 2 diabetic patients who are not on insulin (8,9). This suggests that insulin treatment may unexpectedly worsen prognosis in type 2 diabetic patients following an ischemic insult, and the defect may reside in the myocardium.Uncoupling protein 3 (UCP3) 2 is an inner mitochondrial membrane protein predominantly expressed in brown adipocytes, skeletal muscle, and the heart (10, 11). Uncoupling proteins have a tripartite structure, which has been compared with that of the ADP/ATP carrier of the mitochondrial inner membrane (12). Despite its high sequence homology with the archetypal uncoupling protein 1 and the fact that it can mediate mitochondrial proton leak, the physiological function of UCP3 remains unknown. There is compelling evidence that UCP3 protects the heart from ischemia-reperfusion injury. For example, we and others have recently shown both ex vivo and in vivo that the ...

show abstract

Section: Acute and Chronic Insulin Stimulations Down-regulate Ucp3 Atsupporting

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart

Harmancey

Haight

Watts

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Increased ex-pression of cholesteryl ester transfer protein (CTEP) is linked to decreased HDL levels [33]. This was reversed by intensive insulin therapy [34] but appears not to be under the control of thiamine-induced responses. Decreased lipoprotein lipase (LPL) activity is associated with impaired removal and increased plasma concentrations of triglycerides in diabetes [35].…”

Section: Discussionmentioning

confidence: 99%

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

et al. 2004

View full text Add to dashboard Cite

Aims/hypothesis. Cardiovascular disease in diabetes is linked to increased risk of atherosclerosis, increased levels of triglyceride-rich lipoproteins and enhanced hepatic lipogenesis. The hepatic hexosamine pathway has been implicated in signalling for de novo lipogenesis by the liver. In this study, we assessed if decrease of flux through the hexosamine pathway induced by high-dose thiamine therapy counters diabetic dyslipidaemia. Methods. The model of diabetes used was the streptozotocin-induced diabetic rat with maintenance insulin therapy. Normal control and diabetic rats were studied for 24 weeks with and without oral high-dose therapy (7 and 70 mg/kg) with thiamine and benfotiamine. Plasma total cholesterol, HDL cholesterol and triglycerides were determined at 6-week intervals and hepatic metabolites and transketolase activity after death of the rats at 24 weeks.Results. We found that thiamine therapy (70 mg/kg) prevented diabetes-induced increases in plasma cholesterol and triglycerides in diabetic rats but did not reverse the diabetes-induced decrease of HDL. This was achieved by prevention of thiamine depletion and decreased transketolase activity in the liver of diabetic rats. There was a concomitant decrease in hepatic UDP-N-acetylglucosamine and fatty acid synthase activity. Thiamine also normalised food intake of diabetic rats. A lower dose of thiamine (7 mg/kg) and the thiamine monophosphate prodrug benfotiamine (7 and 70 mg/kg) were ineffective. Conclusions/interpretation. High-dose thiamine therapy prevented diabetic dyslipidaemia in experimental diabetes probably by suppression of food intake and hexosamine pathway signalling but other factors may also be involved. Benfotiamine was ineffective.Keywords Cholesterol · Dyslipidaemia · Glycation · Hexosamine · Streptozotocin · Thiamine · Triglycerides Abbreviations: 1,3-bis-PG, 1,3-bisphosphoglycerate · ACC, acetyl-CoA carboxylase · CEL, N ε -(1-carboxyethyl)lysine · CML, N ε -carboxymethyl-lysine · CTEP, cholesteryl ester transfer protein · DAG, diacylglycerol · DHAP, dihydroxyacetonephosphate · F-1,6-bis-P, fructose-1,6-bis-phosphate · FAS, fatty acid synthase · FL, N ε -fructosyl-

show abstract

“…Two strains of CETP-expressing mice have been commonly used to study the impact of CETP expression on lipid metabolism. In humans and in mice expressing the human CETP gene, CETP expression is induced with obesity, is suppressed by acute hyperinsulinemia, and is regulated by ovarian hormones (23)(24)(25)(26). We used mice that constitutively express the simian CETP gene ( 22,27 ) to defi ne how metabolic changes affect HDL composition, independent of alterations in CETP expression.…”

Section: Western Blotsmentioning

confidence: 99%

Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones

Martinez¹,

Emfinger

Overton

et al. 2012

Journal of Lipid Research

View full text Add to dashboard Cite

Impairment in HDL function associated with obesity and elevated serum triglyceride (TG) may be a major contributor to risk of coronary heart disease (CHD) in obese patients, yet mechanisms by which changes in metabolism impair HDL function are not well defi ned ( 1-6 ). Increased TGs in the form of VLDL give rise to low levels of HDL in part due to the actions of cholesteryl ester transfer protein (CETP), which shuttles TG and cholesteryl esters between serum lipoproteins. Because of lipid exchange, elevated serum VLDL leads to TG enrichment of HDL. This TG enrichment reduces the affinity of apolipoprotein A1 (apoA1) for cholesterol, promotes clearance of apoA1, and decreases HDL particle number ( 1, 3, 7 ). In addition, changes in the function of HDL related to infl ammation, coagulation, and reverse cholesterol transport are associated with obesity and metabolic diseases. HDL proteomics have revealed changes in apolipoproteins, infl ammatory proteins, and coagulation proteins in individuals with known Abstract Mechanisms underlying changes in HDL composition caused by obesity are poorly defi ned, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFDfeeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFDinduced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively infl uences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to defi ne how metabolic changes affect HDL composition and function.

show abstract

Cholesteryl ester transfer protein expression is down-regulated in hyperinsulinemic transgenic mice

Cited by 11 publications

References 43 publications

Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart

Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones

Contact Info

Product

Resources

About