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1.
Drugs ; 73(4): 327-39, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23479408

ABSTRACT

Dyslipidemia is one of the key risk factors for cardiovascular disease (CVD) in diabetes mellitus. Despite the mounting clinical trial data, the management of dyslipidemia other than lowering the low density lipoprotein cholesterol (LDL-c) continues to be controversial. The characteristic features of diabetic dyslipidemia are high plasma triglyceride concentration, reduced high density lipoprotein cholesterol (HDL-c) concentration, and increased concentration of small dense LDL particles. These changes are caused by increased free fatty acid flux secondary to insulin resistance and aggravated by increased inflammatory adipokines. The availability of several lipid-lowering drugs and nutritional supplements offers novel and effective options for achieving target lipid levels in people with diabetes. While initiation of drug therapy based on differences in the lipid profile is an option, most practice guidelines recommend statins as first-line therapy. Although the evidence for clinical utility of combination of statins with fibrates or nicotinic acid in reducing cardiovascular events remains inconclusive, the preponderance of evidence suggests that a subgroup who have high triglycerides and low HDL-c levels may benefit from combination therapy of statins and fibrates. The goal of therapy is to achieve at least 30-40 % reduction in LDL-c levels. Preferably the LDL-c should be less than 100 mg/dL in low-risk people and less than 70 mg/dL in those at high risk, including people with established CVD.


Subject(s)
Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/physiopathology , Dyslipidemias/physiopathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Cardiovascular Diseases/etiology , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Clinical Trials as Topic , Diabetes Mellitus, Type 2/drug therapy , Dyslipidemias/drug therapy , Humans , Hypolipidemic Agents/therapeutic use , Prevalence , Risk Factors
2.
Life Sci ; 91(1-2): 64-9, 2012 Jul 26.
Article in English | MEDLINE | ID: mdl-22727790

ABSTRACT

AIMS: Smokers have lower plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) compared with nonsmokers. To determine the molecular basis of this observation, the effect of activation of the aryl hydrocarbon receptor (AhR) on apo A-I gene expression was examined. MAIN METHODS: HepG2 cells were treated with AhR receptor agonists benzo(a)pyrene (BaP) and CAY10465, and AhR receptor antagonist CAY10464 and apo A-I protein, mRNA levels and promoter activity were measured. The effect of nicotine on apo A-I protein secretion was also tested. Using a series or apo A-I gene promoter deletion constructs, a xenobiotic response element (XRE) was identified. KEY FINDINGS: Treatment of HepG2 cells with the AhR receptor agonists BaP and CAY10465, inhibited apo A-I protein synthesis while nicotine, which does not bind AhR had no effect. Benzo(a)pyrene treatment also suppressed apo A-I mRNA and gene promoter activity. Treatment of HepG2 cells with the AhR receptor antagonist CAY10464 reversed the suppressive effect of BaP on apo A-I gene expression. A putative xenobiotic response element (XRE) was identified between nucleotides -325 and -186 (relative to the transcriptional start site, +1). SIGNIFICANCE: These results suggest that the cigarette smoking related environmental contaminant BaP promotes hypoalphalipoproteinemia in part through activation of the hepatic AhR.


Subject(s)
Apolipoprotein A-I/genetics , Hypoalphalipoproteinemias/etiology , Receptors, Aryl Hydrocarbon/metabolism , Smoking/adverse effects , Apolipoprotein A-I/metabolism , Benzopyrenes/pharmacology , Blotting, Western , Cell Line , Gene Deletion , Gene Expression Regulation/drug effects , Humans , Nicotine/pharmacology , Polymerase Chain Reaction , Promoter Regions, Genetic , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/antagonists & inhibitors
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