Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.

Vu‐Dac, Ngoc; Gervois, Philippe; Pineda-Torra, Inés; Fruchart, Jean‐Charles; Kosykh, V. P.; Kooistra, Teake; Princen, H.M.G.; Dallongeville, Jean; Staels, Bart

doi:10.1172/jci1581

Cited by 124 publications

(92 citation statements)

References 55 publications

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“…19 In support of this claim, we observed that the RXR agonist LG100268, but not the antagonist LG100754, stimulated TG synthesis in HepG2 cells. One proposal suggests that PIs alter RXR signaling by inhibiting the synthesis of 9-cis-retinoic acid.…”

Section: Discussionsupporting

confidence: 51%

“…19 To investigate whether retinoids and PIs interact to increase hepatic lipid synthesis, HepG2 cells were treated with NFV in the absence or presence of the RXR agonist LG100268 or the RXR homodimer antagonist LG100754. As shown in Figure 2A, 100 nmol/L LG100754 did not significantly affect TG synthesis.…”

Section: Nfv and Lg100268 Stimulate Lipid Synthesis And Gene Expressimentioning

confidence: 99%

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HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

Lenhard

Croom

Weiel

et al. 2000

ATVB

134

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Abstract-Hyperlipidemia may complicate the use of HIV protease inhibitors (PIs) in AIDS therapy. To determine the cause of hyperlipidemia, the effect of PIs on lipid metabolism was examined with HepG2 liver cells and AKR/J mice. In HepG2 cells, the PIs ABT-378, nelfinavir, ritonavir, and saquinavir stimulated triglyceride synthesis; ritonavir increased cholesterol synthesis; and amprenavir and indinavir had no effect. Moreover, nelfinavir increased mRNA expression of diacylglycerol acyltransferase and fatty acid synthase. The retinoid X receptor agonist LG100268, but not the antagonist LG100754, further increased PI-stimulated triglyceride synthesis and mRNA expression of fatty acid synthase in vitro. In fed mice, nelfinavir or ritonavir did not affect serum glucose and cholesterol, whereas triglyceride and fatty acids increased 57% to 108%. In fasted mice, ritonavir increased serum glucose by 29%, cholesterol by 40%, and triglyceride by 99%, whereas nelfinavir had no effect, suggesting these PIs have different effects on metabolism. Consistent with the in vitro results, nelfinavir and ritonavir increased triglyceride 2-to 3-fold in fasted mice injected with Triton WR-1339, an inhibitor of triglyceride clearance. We propose that PI-associated hyperlipidemia is due to increased hepatic triglyceride synthesis and suggest that retinoids or meal restriction influences the effects of select PIs on lipid metabolism. HAART has been associated with numerous affects on lipid metabolism, including subcutaneous fat wasting, abdominal obesity, insulin resistance, and hyperlipidemia. 2,3 Metabolic complications arising from HAART may be due to drug-drug interactions, exacerbation of preexisting conditions, reconstitution of immune system function, or a combination. 2,3 Studies of hyperlipidemia in HIV-infected persons are complicated because dyslipidemia may occur in the absence of therapy (reviewed in Safrin and Grunfeld 3 ). Although HIV infection itself and treatment with reverse transcriptase inhibitors have been associated with altered metabolism, 2-6 substantial evidence indicates a role for some PIs in causing metabolic complications.PIs are important therapeutically because they inhibit virus release from infected cells, reducing virus proliferation and subsequent infection. 7 The currently available PIs include amprenavir (APV), indinavir (IDV), nelfinavir (NFV), ritonavir (RTV), saquinavir (SQV), and ABT-378 (lopinavir; delivered in combination with RTV to enhance systemic exposure to ABT-378). The antiviral activity among individual PIs is variable and correlates with the ability to inhibit the HIV protease (ie, IC 50 0.10 to 20 nmol/L). Although these drugs contain a synthetic analog of the phenylalanine-proline amino acid sequence cleaved by the HIV protease, structural differences result in unique resistance and metabolic effects for each PI. 7 Initial reports in 1997 indicated that a number of patients developed hyperlipidemia after PI therapy. Several studies specifically implicated RTV, RTV/SQV, or NFV thera...

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Section: Discussionsupporting

confidence: 51%

Section: Nfv and Lg100268 Stimulate Lipid Synthesis And Gene Expressimentioning

confidence: 99%

HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

Lenhard

Croom

Weiel

et al. 2000

ATVB

134

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“…RBP4 is a transporter protein for retinol that serves as a precursor for the synthesis of ligands of the retinoid X receptor and retinoic acid receptor nuclear hormone receptors [19]. In previous studies, retinoids increased the hepatic production of VLDL [20] and elevated the levels of apolipoprotein (apo) C-III [21], a hepatic protein that delays (1) the catabolism of VLDL particles by inhibiting their binding to the endothelial surface and (2) lipolysis by lipoprotein lipase [22]. This may explain the lack of an association between RBP4 and lipoprotein lipase in our study.…”

Section: Discussionmentioning

confidence: 99%

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

et al. 2007

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Aims/hypothesis Retinol-binding protein 4 (RBP4) has recently been reported to be associated with insulin resistance and the metabolic syndrome. This study tested the hypothesis that RBP4 is a marker of insulin resistance and the metabolic syndrome in patients with type 2 diabetes or coronary artery disease (CAD) or in non-diabetic control subjects without CAD. Methods Serum RBP4 was measured in 365 men (126 with type 2 diabetes, 143 with CAD and 96 control subjects) and correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR), components of the metabolic syndrome and lipoprotein metabolism. RBP4 was detected by ELISA and validated by quantitative Western blotting. Results RBP4 concentrations detected by ELISA were shown to be strongly associated with the results gained in quantitative Western blots. There were no associations of RBP4 with HOMA-IR or HbA 1c in any of the groups studied. In patients with type 2 diabetes there were significant positive correlations of RBP4 with total cholesterol, LDL-cholesterol, VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity. In patients with CAD, there were significant associations of RBP4 with VLDLcholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDLcholesterol and plasma triacylglycerol. Conclusions/interpretation RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in male patients with type 2 diabetes or CAD. Independent associations of RBP4 with pro-atherogenic lipoproteins and enzymes of lipoprotein metabolism indicate a possible role of RBP4 in lipid metabolism.

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“…Both fibratesFagonists of peroxisome proliferator-activated receptor alpha (PPARa)Fand retinoidsFpanagonists of the retinoic acid receptors RAR and RXRFwere commonly shown to influence triglyceridemia through changing the expression of apolipoprotein C-III (ApoC-III) gene. 6,7 This gene alone as well as the whole ApoA-I/C-III/A-IV cluster (and most recently its new member, ApoA-V) were associated with dyslipidemia in human populations and animal models 3,8 and were also suggested as putative candidates for hypertriglyceridemia in a genetic model of insulin resistance syndrome, polydactylous (PD/Cub) rat strain [9][10][11][12][13][14] (http:// www.img.cas.cz/fb/, Table 1). Therefore, we examined the effect of fenofibrate and isotretinoin administration on metabolic profile, insulin sensitivity and lipolysis in tissues and the expression of ApoC-III and one of its proposed upstream regulatory genes, hepatocyte nuclear factor-4 (Hnf-4), in the PD/Cub rat strain.…”

Section: Introductionmentioning

confidence: 99%

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

et al. 2004

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OBJECTIVE:To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub). DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days. MEASUREMENTS: Parameters of lipid and carbohydrate metabolismForal glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver. RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/ glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues. CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoidinduced hypertriglyceridemia.

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Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.

Abstract: Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C-III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (

Cited by 124 publications

References 55 publications

HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

HIV Protease Inhibitors Stimulate Hepatic Triglyceride Synthesis

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

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