Pharmacogenetic Model of Retinoic Acid-Induced Dyslipidemia and Insulin Resistance

Krupková, Michaela; Janků, M; Liška, František; Šedová, Lucie; Kazdová, Ludmila; Křenová, D; Křen,; Šeda, Ondřej

doi:10.2217/pgs.09.113

Cited by 18 publications

(12 citation statements)

References 40 publications

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“…RA is a small molecule that can easily pass through the cell membrane, being subsequently transported to the nucleus by cellular RA-binding proteins where it binds the nuclear receptors, retinoic acid receptors (RARs) (19,20). However, complicating the effects of RA on lipid metabolism, a study reported that RA increased adiposity in rats (27) and other cell line studies have shown that RA increased the differentiation of adipocytes (28,29). Levels of RA are regulated by its production via this process or degradation by CYP26 enzymes (21).…”

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confidence: 99%

Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway

et al. 2015

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The endocannabinoid system (ECS) and retinoic acid (RA) signaling have been associated with influencing lipid metabolism. We hypothesized that modulation of these pathways could modify lipid abundance in developing vertebrates and that these pathways could have a combinatorial effect on lipid levels. Zebrafish embryos were exposed to chemical treatments altering the activity of the ECS and RA pathway. Embryos were stained with the neutral lipid dye Oil-Red-O (ORO) and underwent whole-mount in situ hybridization (WISH). Mouse 3T3-L1 fibroblasts were differentiated under exposure to RA-modulating chemicals and subsequently stained with ORO and analyzed for gene expression by qRT-PCR. ECS activation and RA exposure increased lipid abundance and the expression of lipoprotein lipase. In addition, RA treatment increased expression of CCAAT/enhancer-binding protein alpha. Both ECS receptors and RA receptor subtypes were separately involved in modulating lipid abundance. Finally, increased ECS or RA activity ameliorated the reduced lipid abundance caused by peroxisome proliferator-activated receptor gamma (PPARγ) inhibition. Therefore, the ECS and RA pathway influence lipid abundance in zebrafish embryos and have an additive effect when treated simultaneously. Furthermore, we demonstrated that these pathways act downstream or independently of PPARγ to influence lipid levels. Our study shows for the first time that the RA and ECS pathways have additive function in lipid abundance during vertebrate development.

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confidence: 99%

Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway

et al. 2015

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“…The role of RA, a more oxidized retinoid produced from RAL, in lipid metabolism is controversial. RA used clinically is known to induce hypertriglyceridemia (25,26). Two lipogenic genes, SREBP-1 and FAS, were induced in hepatic cells by all-trans-RA in vitro (27), whereas they were dramatically suppressed in vivo (28).…”

Section: Discussionmentioning

confidence: 99%

Lipid Emulsion Administered Intravenously or Orally Attenuates Triglyceride Accumulation and Expression of Inflammatory Markers in the Liver of Nonobese Mice Fed Parenteral Nutrition Formula

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Hao

Wray

et al. 2013

The Journal of Nutrition

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The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4-5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 μg/g orally), LE (200 μL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy.

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“…Blood samples were drawn after overnight fasting from the tail vein. Using high performance liquid chromatography (HPLC), triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles were determined as described previously [9] , [22] . Then the rats were sacrificed and the weights of heart, liver, kidneys, adrenals, epididymal and retroperitoneal fat pads were determined.…”

Section: Methodsmentioning

confidence: 99%

“…Several recent studies identified genetic polymorphisms contributing to variation in lipoprotein diameters in distinct geoethnic groups [6] , [12] or patterns of lipoprotein subfraction distribution [13] – [16] . As the TG and C content across the lipoprotein spectrum is substantially influenced by both genetic factors and environmental effects including diet [17] – [19] and medication [20] – [22] , mammalian models have been successfully used for reduction of complexity in the detailed analyses of their genetic determinants [23] , [24] . Already in 1996, an association study of the major lipoprotein subfractions was performed in 30 recombinant inbred HXB BXH strains derived from spontaneously hypertensive (SHR) and congenic Brown Norway (BN- Lx ) rat strains [25] .…”

Section: Introductionmentioning

confidence: 99%

Genomic Determinants of Triglyceride and Cholesterol Distribution into Lipoprotein Fractions in the Rat

et al. 2014

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The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8–13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains.

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Pharmacogenetic Model of Retinoic Acid-Induced Dyslipidemia and Insulin Resistance

Cited by 18 publications

References 40 publications

Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway

Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway

Lipid Emulsion Administered Intravenously or Orally Attenuates Triglyceride Accumulation and Expression of Inflammatory Markers in the Liver of Nonobese Mice Fed Parenteral Nutrition Formula

Genomic Determinants of Triglyceride and Cholesterol Distribution into Lipoprotein Fractions in the Rat

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