The different effect of pioglitazone as compared to insulin on expression of hepatic and intestinal genes regulating post-prandial lipoproteins in diabetes

Department of Diabetes and Endocrinology, Trinity College, Dublin 2, Ireland.
Atherosclerosis (Impact Factor: 3.99). 08/2007; 193(2):343-51. DOI: 10.1016/j.atherosclerosis.2006.09.031
Source: PubMed


This study investigates lipoprotein composition in diabetes before and after treatment with insulin or pioglitazone and its relationship to gene expression of five genes found in liver and intestine which are involved in cholesterol homeostasis. Thirty zucker diabetic fatty fa/fa and 10 lean rats were examined. mRNA for 3-hydroxy3-methylglutaryl coenzyme A reductase (HMGCoA), microsomal triglyceride transfer protein (MTTP), Niemann Pick C1-like 1 (NPC1L1) and ATP binding cassette transporters (ABC) G5 and G8 was determined using real-time, reverse transcriptase (RT-PCR). Cholesterol, triglyceride, apo B48 and apo B100 were elevated in chylomicrons and very low density lipoproteins (VLDL) of untreated diabetic animals (p<0.02). For similar blood glucose pioglitazone was more effective than insulin in normalising the lipoproteins. In diabetic animals, HMGCoA reductase, MTTP and NPC1L1 mRNA were significantly elevated (p<0.02) and ABCG5 and ABCG8 were significantly reduced (p<0.02) in the liver. Pioglitazone significantly reduced hepatic MTTP and NPC1L1 mRNA (p<0.0001) and significantly increased ABCG5 and G8 mRNA (p<0.0001) as compared to insulin. In conclusion diabetes was associated with major changes in mRNA levels of proteins involved in the regulation of post-prandial lipoproteins. Pioglitazone and insulin have different effects on post-prandial lipoprotein metabolism in part due their effect on genes regulating cholesterol synthesis and lipoprotein assembly.

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    • "They found that levels were partially normalised on insulin supplementation. We have shown that ABCG5 and G8 were reduced by more than 50% in the intestine of zucker diabetic fa/fa rats compared with lean rats although this did not reach statistical significance [41]. Insulin treatment caused a non-significant increase in ABCG5 and G8 mRNA. "
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    International journal of vascular medicine 01/2012; 2012(2090-2824):784536. DOI:10.1155/2012/784536
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    • "Administration of high-doses of 17β-estradiol (6 µg/day) to ovariectomized AKR or C57L mice increases NPC1L1 mRNA expression in duodena and jejuna, but not ilea (Duan et al., 2006). Intestinal and hepatic NPC1L1 mRNA levels are significantly higher in streptozotosin-induced diabetic versus nondiabetic rats (Lally et al., 2007), and in Zucker diabetic fatty versus lean rats (Lally et al., 2007). NPC1L1 mRNA levels are also ~2-fold higher in the intestinal biopsy samples from type 2 diabetic patients than nondiabetic patients (Lally et al., 2006, Lally et al., 2007). "
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    Sub-cellular biochemistry 01/2010; 51:337-80. DOI:10.1007/978-90-481-8622-8_12
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    ABSTRACT: La résistance à l’insuline et le diabète de type 2 (DT2) sont caractérisés par une hyperlipidémie. Le but de cette étude est de déterminer si le DT2 contribue au dérèglement du métabolisme du cholestérol au niveau du petit intestin et du foie du Psammomys obesus, un modèle animal nutritionnel d’induction de la résistance à l’insuline et du DT2. L’absorption intestinale du cholestérol est diminuée chez les animaux diabétiques. Cette diminution est associée à une baisse (i) de l’expression génique et protéique de NPC1-L1 qui joue un rôle primordial dans l’absorption du cholestérol au niveau des entérocytes; et (ii) de l’ARNm de l’ABCA1 responsable de l’efflux de cholestérol des cellules intestinales à l’apolipoprotéine A-I et aux HDLs. En ce qui a trait aux transporteurs SR-B1 et Annexin II, aucune différence n’a été observée au niveau intestinal. Toutefois, une diminution significative de l’expression génique de l’ABCG5, un intervenant majeur dans la sécrétion du cholestérol des entérocytes vers la lumière intestinale, est mesurée chez les animaux diabétiques. De plus, l’expression protéique est diminuée pour le PCSK9 et augmentée pour le LDLr au niveau du jéjunum, tandis que la quantité de protéine de l’enzyme HMG-CoA réductase est régulée à la baisse chez les Psammomys obesus diabétiques. Finalement, de tous les facteurs de transcription testés seule une augmentation de LXR et une diminution de PPAR/δ sont détectées au niveau de l’intestin. Au niveau hépatique, il y a (i) une augmentation de la masse protéique de NPC1-L1, SR-BI et Annexin II; (ii) une élévation l’ARNm de SR-BI; (iii) une diminution du contenu protéique de ABCG8 et de l’expression génique de l’ABCG5 et de l’ABCA1; et (iv) une élévation de l’ARNm de LXR et de PPAR/δ, tout comme une baisse de l’expression protéique de SREBP-2. Somme toute, nos résultats montrent que le développement du diabète de type 2 chez le Psammomys obesus entraîne un changement dans la machinerie intra-entérocytaire et hépatocytaire, qui mène à un dérèglement de l’homéostasie du cholestérol. Insulin resistance and type 2 diabetes (T2D) are characterized by hyperlipidemia. The aim of the present study was to elucidate whether T2D contributes to abnormal cholesterol homeostasis in the small intestine and liver of Psammomys obesus, a model of nutritionally induced insulin resistance and type 2 diabetes. Diabetic animals exhibited a lower intestinal cholesterol uptake, which was associated with a decrease in (i) the gene and protein expression of NPC1L1, which plays a pivotal role in cholesterol incorporation in the enterocytes; and (ii) mRNA of ABCA1 that mediates cholesterol efflux from intestinal cells to apolipoprotein A-I and HDL. No changes were observed in the other intestinal transporters SR-BI and Annexin II. On the other hand, in diabetic animals, a significant mRNA decrease was noticed in ABCG5 responsible for the secretion of absorbed cholesterol back into the lumen. Furthermore, jejunal PCSk9 protein was diminished and LDLr was raised, along with a significant downregulation in jejunal HMG-CoA reductase in diabetic Psammomys obesus. Finally, among the transcription factors tested, only an increase in LXR and a decrease in PPAR/δ were detected in the intestine. In the liver, there was (i) an augmentation in the protein mass of NPC1L1, SR-BI and Annexin II; (ii) an upregulation of SR-BI mRNA; (iii) a fall in ABCG8 protein content, ABCG5 mRNA and ABCA1 mRNA; and (iv) an augmentation in LXR and PPAR/δ mRNA, as well as a drop in SREBP-2 protein. Overall, our findings show that the development of type 2 diabetes in Psammomys obesus modifies the whole intra-enterocyte and hepatocyte machinery, causing alterations in cholesterol homeostasis.
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