Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors evaluated the lipid profile of children with a positive family history of coronary heart disease (CHD), cerebrovascular disease (CVD), or hyperlipidemia and compared them with controls in order to identify risk indicators for atherosclerosis. A group of 315 children (group A) aged more than 2 years old with a positive family history were evaluated for serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B100 (ApoB100), apolipoprotein A1 (Apo A1), and lipoprotein (a) (Lp[a]). These values were compared with the levels of a control group of 214 children of comparable age (group B). The median age of children in groups A and B was 10.6 (range 2.3-16) and 9.8 (range 3-13.7) years of age, respectively. Among these children, 196 (52%), 47 (12.5%), and 72 (19.1%) had a positive family history of CHD (group A1), cerebrovascular disease (CVD) (group A2), and hypercholesterolemia (group A3), respectively. We identified 8 children with genetically determined dyslipidemia: 2 children with homozygous and 6 with heterozygous familial hypercholesterolemia. Children in group A3 had significantly higher concentrations of TC, TG, LDL-C, and ApoB100 and lower concentrations of Apo A1 compared with controls, while no significant differences were found in concentrations of lipid variables among children of group A1, A2, and A3. Significant differences were also noted in the concentrations of TC, LDL-C, and Lp(a) between children of group A1 and controls. Screening the progeny of young patients with CHD or familial hypercholesterolemia can identify children at excessive risk for future vascular disease.
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PMID:Lipid profile of children with a family history of coronary heart disease or hyperlipidemia: 9-year experience of an outpatient clinic for the prevention of cardiovascular diseases. 1607 21

The link between hepatic insulin signaling and apolipoprotein B (apoB) production has important implications in understanding the etiology of metabolic dyslipidemia commonly observed in insulin-resistant states. Recent studies have revealed important translational mechanisms of apoB mRNA involving the 5' untranslated region (5'UTR) and insulin-mediated translational suppression via an insulin-sensitive RNA binding protein. Here, we have investigated the role of the protein kinase C (PKCs) signaling cascade in the regulation of apoB mRNA translation, using a series of chimeric apoB UTR-luciferase constructs, in vitro translation of UTR-luciferase cRNAs, and metabolic labeling of intact HepG2 cells. The PKC activator, phorbol 12-myristate 13-acetate (PMA), increased luciferase expression of constructs containing the apoB 5' UTR whereas treatment with Bis-I, a general PKC inhibitor or Go6976, a more specific PKC alpha/beta inhibitor, decreased expression, under both basal and insulin-treated conditions. These effects were confirmed to be translational in nature based on in vitro translation studies of T7 apoB UTR-luciferase constructs transcribed and translated in vitro in the presence of HepG2 cytosol treated with insulin or signaling modulators. Mobility shift experiments using cytosol treated with either PKC inhibitor (Bis-I) or activator (PMA) showed parallel changes between translation of apoB 5'UTR-luciferase constructs and the binding of a protein(s) complex migrating around 110 kDa to the apoB 5' UTR. ApoB mRNA levels were unaltered under these conditions based on real-time PCR analysis. Bis-I and Go6976 were both able to significantly decrease newly synthesized apoB100 protein in the presence or absence of insulin. Overall, the data suggests that PKC activation may induce increased mRNA translation and synthesis of apoB100 protein through a mechanism involving the interaction of trans-acting factors with the apoB 5'UTR. We postulate potential links between PKC activation as seen in insulin-resistant/diabetic states, enhanced translation of apoB mRNA, and hepatic VLDL-apoB overproduction.
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PMID:Translational control of apolipoprotein B mRNA via insulin and the protein kinase C signaling cascades: evidence for modulation of RNA-protein interactions at the 5'UTR. 1728 85

Apolipoprotein B-100 (ApoB) is the main protein of the atherogenic lipoproteins and plasma ApoB levels reflect the total numbers of atherogenic lipoproteins. Induction of insulin resistance was accompanied by a considerable rise in the production of hepatic very low density lipoprotein (VLDL) containing ApoB and triglyceride. Increased plasma levels of ApoB and triglyceride in VLDL are common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus. Thus, we investigate whether phorbol 12-myristate-13-acetate (PMA)-induced insulin resistance affects the increase of ApoB secretion. PMA increased ApoB secretion and transcriptional level of microsomal triglyceride transfer protein (MTP). PMA treatment also resulted in increase of insulin receptor substrate 1 (IRS1) serine312 (Ser312) and serine1101 (Ser1101) phosphorylation and induction of IRS1 degradation. Additionally, PMA induced activation of c-jun N-terminal kinase (JNK) and protein kinase C (PKC) isoforms (alpha, betaI, delta, zeta, theta), and reduced AKT8 virus oncogene cellular homolog (AKT) activation in a time dependent manner. PMA-induced ApoB secretion, MTP promoter activities, and IRS1 degradation was significantly decreased by treatment of JNK and PKCs inhibitors. Orthovanadate, a potent tyrosine phosphatase inhibitor, increased tyrosine phosphorylation of IRS1 and decreased ApoB secretion of Chang liver cells although PMA was co-treated. From the results, it was concluded that PMA-induced insulin resistance, through induction of serine phosphorylation of IRS1 mediated by activated JNK and PKCs, increases ApoB secretion in Chang liver cells.
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PMID:Secretion of atherogenic risk factor apolipoprotein B-100 is increased by a potential mechanism of JNK/PKC-mediated insulin resistance in liver cells. 1764 75

Hepatic overproduction of apolipoprotein B (apoB)-containing lipoproteins is characteristic of the dyslipidemia associated with insulin resistance. Recently, we demonstrated that the flavonoid naringenin, like insulin, decreased apoB secretion from HepG2 cells by activation of both the phosphoinositide-3-kinase (PI3-K) pathway and the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK(erk)) pathway. In the present study, we determined whether naringenin-induced signaling required the insulin receptor (IR) and sensitized the cell to the effects of insulin, and whether the kinetics of apoB assembly and secretion in cells exposed to naringenin were similar to those of insulin. Immunoblot analysis revealed that insulin stimulated maximal phosphorylation of IR and IR substrate-1 after 10 min, whereas naringenin did not affect either at any time point up to 60 min. The combination of naringenin and submaximal concentrations of insulin potentiated extracellular-regulated kinase 1/2 activation and enhanced upregulation of the LDL receptor, downregulation of microsomal triglyceride transfer protein expression, and inhibition of apoB-100 secretion. Multicompartmental modeling of apoB pulse-chase studies revealed that attenuation of secreted radiolabeled apoB in naringenin- or insulin-treated cells was similar under lipoprotein-deficient or oleate-stimulated conditions. Naringenin and insulin both stimulated intracellular apoB degradation via a kinetically defined rapid pathway. Therefore, naringenin, like insulin, inhibits apoB secretion through activation of both PI3-K and MAPK(erk) signaling, resulting in similar kinetics of apoB secretion. However, the mechanism for naringenin-induced signaling is independent of the IR. Naringenin represents a possible strategy for reduction of hepatic apoB secretion, particularly in the setting of insulin resistance.
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PMID:Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor. 1858 69

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.
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PMID:Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity. 1865 87

Plasma VLDL accumulation in Gram-negative sepsis is partly ascribed to an increased hepatic VLDL production driven by pro-inflammatory cytokines. We previously showed that hepatocytes of the Kupffer cell (KC)-rich periportal area are major contributors to enhanced VLDL production in lipopolysaccharide (LPS)-injected rats. However, it remains to be established whether KC generated products directly affect the number (apoB) and composition of secreted VLDL. Using rat primary cells, we show here that hepatocytes respond to stimulation by soluble mediators released by LPS-stimulated Kupffer cells with enhanced secretion of apoB and triglycerides in phospholipid-rich VLDL particles. Unstimulated KC products also augmented the secretion of normal VLDL, doubling apoB mRNA abundance. IL-1beta treatment resulted in concentration-dependent increases of hepatocyte apoB mRNA and protein secretion, increases that were greater, but not additive, when combined with IL-6 and TNF-alpha. Lipid secretion and MTP mRNA levels were unaffected by cytokines. In summary: (i) enhanced secretion of phospholipid-rich VLDL particles is a net hepatocyte response to LPS-stimulated KC products, which gives a clue about the local role of Kupffer cells in septic dyslipidemia induction; and (ii) pro-inflammatory cytokines act redundantly to enhance apoB secretion involving translational apoB up-regulation, but other humoral components or KC mediators are necessary to accomplish increased lipid association.
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PMID:Kupffer cell products and interleukin 1beta directly promote VLDL secretion and apoB mRNA up-regulation in rodent hepatocytes. 1866 11

The aim was to study the mechanisms involved in the dyslipidemia associated with lipodystrophy in HIV infected patients on antiretroviral therapy (ART). We investigated the in vivo kinetics of apolipoprotein B100 (apoB) containing lipoproteins using a 14 h primed constant infusion of [5,5,5, (2)H(3)] leucine and compartmental modelling in normolipidemic without lipodystrophy (7 patients, NLD) or dyslipidemic with lipodystrophy (7 patients, LD) treated with ART. Subjects in group LD showed higher plasma triglycerides (5.73+/-3.58 vs 1.29+/-0.54 g/L, p<0.005), total cholesterol (2.98+/-0.95 vs 1.74+/-0.26 g/L, p<0.05), apoB (1.49+/-1.11 vs 0.51+/-0.11 g/L, p<0.005) and apolipoprotein CIII in apoB containing lipoproteins (117.7+/-42.2 vs 22.6+/-23.9 g/L, p<0.005). LD subjects exhibited an insulin resistant as observed by higher HOMA (3.44+/-1.62 vs 1.60+/-0.61, p<0.05). They exhibited an increase in VLDL (1.24+/-0.33 vs 0.80+/-0.21 mg/kg/h, p<0.05), decrease in IDL (0.20+/-0.10 vs 0.48+/-0.24 mg/kg/h, p<0.05) and no difference in LDL (0.38+/-0.19 vs 0.45+/-0.25 mg/kg/h) production rate. LD subject also showed a dramatic decrease in transformation of VLDL to IDL (0.013+/-0.010 vs 0.258+/-0.206 h(-1), p<0.005) and IDL to LDL (0.088+/-0.093 vs 0.366+/-0.189 h(-1), p<0.05) and a decrease in fractional catabolic rate (FCR) of VLDL (0.199+/-0.132 vs 0.555+/-0.398 h(-1), p<0.05), IDL (0.110+/-0.08 vs 0.523+/-0.275 h(-1), p<0.05) and LDL (0.010+/-0.005 vs 0.025+/-0.014 h(-1), p<0.05). These disturbances, overproduction and an overall delayed catabolism of apoB, are similar to those observed using the same protocol in insulin resistant subjects. Our study suggests that metabolic disturbance of apoB100 observed in lipodystrophic HIV in combined antiretroviral therapy are consecutive to insulin resistance induced by the treatment.
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PMID:Disturbance of apolipoprotein B100 containing lipoprotein metabolism in severe hyperlipidemic and lipodystrophic HIV patients on combined antiretroviral therapy: evidences of insulin resistance effect. 1899 38

To determine the relative contribution of obesity and/or insulin resistance (IR) in the development of dyslipidemia in chronic kidney disease (CKD), we investigated the transport of apolipoprotein (apo) B-100 in nonobese, nondiabetic, nonnephrotic CKD subjects and healthy controls (HC). We determined total VLDL, VLDL(1), VLDL(2), intermediate density lipoprotein (IDL), and LDL-apoB-100 using intravenous D3-leucine, GC-MS, and multicompartmental modeling. Plasma apoC-III and apoB-48 were immunoassayed. In this case control study, we report higher plasma triglyceride, IDL-, VLDL-, VLDL(1)-, and VLDL(2)-apoB-100 concentrations in CKD compared with HC (P < 0.05). This was associated with decreased fractional catabolic rates [FCRs (pools/day)] [IDL:CKD 3.4 (1.6) vs. HC 5.0 (3.2), P < 0.0001; VLDL:CKD 4.8 (5.2) vs. HC 7.8 (4.8), P = 0.038; VLDL(1):CKD 10.1 (8.5) vs. HC 29.5 (45.1), P = 0.007; VLDL(2):CKD 5.4 (4.6) vs. HC 10.4 (3.4), P = 0.001] with no difference in production rates. Plasma apoC-III and apoB-48 were significantly higher in CKD (P < 0.001) and both correlated with impaired FCRs of VLDL, VLDL(1), and VLDL(2) apoB-100 (P < 0.05). In CKD, apoC-III concentration was the only independent predictor of clearance defects in VLDL and its subfractions. Moderate CKD in the absence of central adiposity and IR is associated with mild hypertriglyceridemia due to delayed catabolism of triglyceride rich lipoproteins, IDL, and VLDL, without changes in production rate. Altered apoC-III metabolism may contribute to dyslipidemia in CKD, and this requires further investigation.
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PMID:Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III. 1954 64

PTMs, such as glycosylation and phosphorylation of apolipoprotein B100 (apoB), are known to be involved with modulating the metabolism of apoB-containing lipoproteins. Current evidence suggests that intracellular and extracellular PTM of apoB are associated with various disorders such diabetes, dyslipidemia and atherosclerosis. The ability to identify and characterize the specific PTM of apoB correlating to specific pathologies may improve our understanding of the underlying molecular mechanisms regulating apoB metabolism. We have developed an assay to detect PTM and/or conformational changes in apoB isolated from the media of HepG2 cells. Using trypsin digestion in conjunction with 2-DE and Western blotting, a 2-D peptide fragment profile of apoB was established. The 2-D apoB profile was composed of a number of trypsin-generated fragments having a molecular mass between 10 and 188 kDa and a wide spectrum of isoelectric points. The 2-D apoB profile obtained from the media of HepG2 cells treated in the presence of agents (tunicamycin and glucosamine) known to modulate the PTM of apoB was distinct from that of control cells. Identifying changes in the 2-D apoB profile has the potential to not only provide insight into the underlying mechanisms regulating the metabolism of apoB-containing lipoproteins but may also have important implications for the development of novel diagnostic tools and/or future therapeutic agents.
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PMID:Development of a 2-D apoB peptide profile to detect conformational changes associated with apoB-containing lipoproteins. 1958 22

Metabolic syndrome, diabetes and obesity are frequently associated with hypertriglyceridemia, hypercholesterolemia and low HDL levels, a phenotype known as atherogenic dyslipidemia. Atherogenic dyslipidemia and hypertriglyceridemia are frequently treated with fibric acid derivatives which activate the nuclear receptor PPAR-alpha leading to reduce plasma triglycerides and an increase in HDL cholesterol levels. The mechanism by which activation of PPAR-alpha with fibrates improves the plasma lipid profile in patients with atherogenic dyslipidemia and hypertriglyceridemia has been examined in several small studies measuring lipoprotein kinetics. The results of these studies indicate that the changes in lipoprotein metabolism observed in response to fibrate treatment vary according to lipoprotein phenotype. In general, fibrates act to reduce VLDL apoB-100 through enhanced fractional catabolism (clearance) of VLDL apoB-100 with additional effects on reducing VLDL apoB-100 production. LDL apoB-100 levels generally decrease in response to fibrates due to increased LDL fractional catabolism except in those patients with high to very high plasma triglyceride levels (>400mg/dL). Fibrates also increase HDL apoA-I and apoA-II levels by enhancing apoA-I and apoA-II production, although this is partially counteracted by increasing fractional catabolism of these apolipoproteins. The potent and specific PPAR-alpha agonist LY518674, reduced VLDL apoB-100 levels through enhanced fractional catabolism similar to what is seen with fibrates. In contrast to fibrates, LY518674 did not change HDL apoA-I levels in response to due to an increased turnover of apoA-I where an increased fractional catabolic rate entirely counteracted the increase in apoA-I production. The changes in apoB metabolism in response to PPAR-alpha activation with fibrates and specific PPAR-alpha agonists would be expected to reduce the risk of cardiovascular disease. However, the benefit of the enhanced turnover of HDL apoA-I in response to PPAR-alpha activation remains to be determined.
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PMID:The effect of PPAR-alpha agonism on apolipoprotein metabolism in humans. 2000 15


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