Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

STANDEVEN, ANDREW M.; BEARD, RICHARD L.; JOHNSON, ALAN T.; BOEHM, MARCUS F.; ESCOBAR, MARIA; HEYMAN, RICHARD A.; CHANDRARATNA, ROSHANTHA A. S.

doi:10.1093/toxsci/33.2.264

Cited by 18 publications

(25 citation statements)

References 19 publications

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“…Similar elevations have been described in humans and rodents treated with 13-cis-RA (Gerber and Erdman, 1980;Bershad et al, 1985;Gustafson et al, 1990;Barth et al, 1993;Standeven et al, 1996;Altman et al, 2002;Stoll et al, 2004). Gerber and Erdman (1980) reported that all-trans-RA was more effective at inducing hypertriglyceridemia in male rats than was 13-cis-RA and that this was independent of the route of exposure (dietary or i.p.…”

supporting

confidence: 62%

“…Gustafson et al (1990) reported that male rats administered approximately 50 mg kg −1 of 13-cis-RA orally exhibited increased plasma triglycerides as early as 24 h after the first day of treatment. Similarly, others reported an increase of serum triglycerides in male rats after the first day of oral gavage with 40 mg kg −1 of 13-cis-RA (Standeven et al, 1996).…”

mentioning

confidence: 64%

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Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid

Cisneros¹,

Gough²,

Patton³

et al. 2005

J. Appl. Toxicol.

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Currently used to treat severe acne, 13-cis-retinoic acid (13-cis-RA) is under investigation for its anticancer effects as is the isomer, all-trans-retinoic acid (all-trans-RA). Here, the effects of oral 13-cis-RA or all-trans-RA treatment on serum chemistry, leptin and adiponectin levels were evaluated. Adult Sprague-Dawley rats were gavaged once daily for 7 consecutive days with 13-cis-RA (7.5 or 15 mg kg(-1)), all-trans-RA (10 or 15 mg kg(-1)) (n=24/sex/dose), or soy oil (n=16/sex) and blood was sampled 30-480 min after the last gavage. The body weight was unaffected; however, the liver/body weight ratios were increased by both doses of all-trans-RA. Sex differences were noted for levels of cholesterol, creatine, triglycerides, albumin, alanine aminotransferase and total protein. Both doses of all-trans-RA reduced albumin levels to approximately 90% of the control and total protein levels to approximately 93% of the control while substantially elevating triglyceride levels to approximately 66%-99% above the control. Additionally, triglyceride levels of the 15 mg kg(-1) 13-cis RA group were approximately 62% higher than the controls and total protein levels were approximately 5% less. Glucose levels were affected by sex and RA treatment in that males treated with 15 mg kg(-1) of 13-cis-RA or 10 mg kg(-1) all-trans-RA had lower (13%-19%) levels than the same-sex controls; however, females were not similarly affected. Neither 13-cis-RA nor all-trans-RA treatment had significant effects on the levels of blood urea nitrogen, aspartate amino transferase, leptin or adiponectin. On a mg kg(-1) basis, all-trans-RA was more potent than 13-cis-RA. These results replicate previous findings of RA-induced increased triglyceride levels. Additionally, several new findings indicate there may be sex-specific effects of RA treatment. Finally, neither treatment appeared to alter the typical diurnal cycles of these endpoints.

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supporting

confidence: 62%

mentioning

confidence: 64%

Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid

Cisneros¹,

Gough²,

Patton³

et al. 2005

J. Appl. Toxicol.

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“…Moreover, high doses of retinoids can induce hypertriglyceridemia in rats and humans, an effect that appears to involve both increased hepatic production of VLDL and suppression of lipoprotein lipase activity in peripheral tissues (see [55]). Of note, retinoid-induced hypertriglyceridemia has been attributed to RAR activation [64], as well as to the ability of retinoids to activate the LXR:RXR heterodimer on the promoter of lipogenic genes [50]. In keeping, RA was shown to induce SREBP-1c and FAS expression in HepG2 cells likely by enhancing the activity of LXR:RXR heterodimers [22], and retinoids were shown to induce SCD1 expression likely by activating RAR [23].…”

Section: Discussionmentioning

confidence: 97%

Retinoic Acid Treatment Enhances Lipid Oxidation and Inhibits Lipid Biosynthesis Capacities in the Liver of Mice

Amengual

Ribot

Bonet

et al. 2010

Cell Physiol Biochem

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Vitamin A, mainly as retinoic acid (RA), is known to affect the development and function of adipose tissues. Treatment with RA reduces body weight and adiposity independent of changes in food intake in mice. Lipid metabolism in liver can have a major impact on whole body adiposity. The aim of this work was to investigate the effects of an in vivo treatment with RA on hepatic lipid metabolism in mice. Adult, standard diet-fed mice were treated with different doses of all-trans RA or vehicle (subcutaneous injection) for 4 days before sacrifice. Food intake and body weight changes during treatment were determined, as well as adiposity, liver composition, levels of circulating metabolites and lipoproteins and expression levels of key mRNA species in liver following sacrifice. RA treatment resulted in reduced body weight and adiposity, as expected. In the liver, RA treatment triggered an increase in the mRNA expression levels of peroxisome proliferator-activated receptor alpha, retinoid X receptor alpha, uncoupling protein 2, liver-type carnitine palmitoyltransferase 1, and carnitine/acylcarnitine carrier, and a reduction in the mRNA expression levels of sterol regulatory element binding protein 1c and fatty acid synthase. Consistent with the changes in gene expression, hepatic triacylglycerol content and circulating VLDL fraction were reduced and levels of circulating ketone bodies increased after RA treatment. These results point to a capacity of active vitamin A forms to shift liver lipid metabolism in vivo towards increased catabolism and reduced lipogenesis. These effects might contribute to the reduction of adiposity brought about by RA treatment.

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“…Thus, the systemic absorption of the RAR antagonist will be expected to be minimal and will not interfere with the therapeutic activity of the systemic retinoid drug. Compound 48 also antagonized the hypertriglyceridemia (STANDEVEN et al 1996b) and the premature epiphyseal plate closure (STANDEVEN et al1996c) produced by systemic RAR agonists. The use of potent synthetic retinoids at high doses in a variety of clinical applications such as chemotherapy is likely to lead to more incidents of acute retinoid intoxication, including life-threatening pancreatitis associated with severe hypertriglyceridemia.…”

Section: Rar Antagonists and Inverse Agonistsmentioning

confidence: 96%

RAR-Selective Ligands: Receptor Subtype and Function Selectivity

Beard¹,

Chandraratna²

1999

Retinoids

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Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

Cited by 18 publications

References 19 publications

Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid

Serum levels of albumin, triglycerides, total protein and glucose in rats are altered after oral treatment with low doses of 13-cis-retinoic acid or all-trans-retinoic acid

Retinoic Acid Treatment Enhances Lipid Oxidation and Inhibits Lipid Biosynthesis Capacities in the Liver of Mice

RAR-Selective Ligands: Receptor Subtype and Function Selectivity

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