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Physiopathologie des Dyslipidémies

The work of our team is dedicated to the study of the pathophysiology of dyslipidemia in humans, mostly dyslipidemia associated with diabetes and insulin-resistance. The group of researches includes scientists and also physicians, who are working on both sides (clinic and research). This allows us to perform many studies in humans (in vivo and ex vivo) and to combine them with animals and in vitro studies.

Notre thématique de recherche :

The majority of our work during the four past years has been dedicated to the pathophysiology of diabetic dyslipidemia and the effects of treatments on this dyslipidemia.

As far as the pathophysiology of diabetic dyslipidemia is concerned, we have shown, in humans, using kinetic studies, that plasma adiponectin is inversely associated with HDL catabolism, explaining 42% of its variance. This suggests a direct role of adiponectin on HDL metabolism.

In a large population of patients with type 2 diabetes, we have studied the association between liver fat content (evaluated quantitatively by proton spectroscopy) and lipid metabolism. We have shown that liver fat was independently associated with hypertriglyceridemia (but not with low HDL-chol.) and hypoadiponectinemia with low cholesterol (but not with hypertriglyceridemia), suggesting the occurrence of two independent pathophysiological mechanisms accounting for diabetic dyslipidemia.

We have also performed several studies on the endothelium dependent vasorelaxant effect of HDL particles, using rabbit aorta rings. We have shown that HDLs from patients with type 2 diabetes, type 1 diabetes and from non-diabetic individuals with abdominal obesity, have lost the endothelium vasorelaxant effect that is usually observed in healthy normolipidemix and normoglycemix control subjects. This may be an additional factor responsible for increased CV risk in these populations.

As far as the effets of treatments on diabetic dyslipidemia are concerned, we have shown, in patients with type 2 diabetes, that rosuvastatin 20 mg increases not only LDL catabolism but also VLDL1, VLDL2 and IDL catabolism and reduces the production rate of VLDL1. In addition, rosuvastatin reduces HDL catabolism leading to increase its plasma residence time.

These kinetic modification induced by rosuvastatin may be beneficial for prevention of atherosclerosis, in type 2 diabetic patients. In another kinetic study, we have demonstrated, in patients with type 1 diabetes, that HDL metabolism is not modified by the replacement of subcutaneous insulin infusion by intraperitoneal insulin infusion, which mimic the « physiologic » portal insulin delivery to the liver. Using animal and in vitro studies, we have shown that pioglitazone and rosiglitazone have direct, but different effects on liver lipid metabolism :

  • Pioglitazone, but not rosiglitazone, reduces HDL uptake by the liver by reducing hepatic lipase activity and Sr-B1 (HDL receptor) expression.
  • In contrast, rosiglitazone, but not pioglitazone, increases liver lipogenesis.

We have also studied the effect of inactivation of the endocannabinoid system on lipid metabolism in diet-induced receptor (CB1R) on lipid metabolism, at liver and adipose tissue sites. CB1R blockade induced gene expression of SR-B1 and Hepatic Lipase, and was associated with increase in HDL-CE uptake. Concomitantly, expression of CB1R, which was strongly increased in liver and adipose tissue of HSHF mice, was totally normalized by the treatment suggesting that the metabolic improvements observed are likely to be mediated by the blockade of these receptors. Furthermore, CB1R blockade was able to abolish the increase in the expression of genes involved in transport, synthesis oxidation and release of FA, observed in visceral AT of obese mice.

  • Institut National de la Santé Et de la Recherche Médicale
  • Tirets de séparation
  • L'Inserm en région Grand-Est
Soutiens :

Agence Nationale de la Recherche Agrosup Dijon Fondation ARC pour la recherche sur le cancer Cent Pour Sang La Vie CHU Dijon Centre Georges François LECLERC
Conseil Régional de Bourgogne Le Fonds européen de développement régional Institut National du Cancer ELA Association Européenne contre les leucodystrophies EPHE : Dijon - Université de Bourgogne Faculté de Médecine de Dijon
UFR Pharmacie - uB, Dijon Fondation de France Fondation pour la Recherche Médicale en France Laboratoire d’excellence - LipSTIC Dijon La Ligue Contre le Cancer Société française d'hématologie