Lipid transfer proteins and lipoprotein metabolism

Cholesteryl ester transfer protein (CETP) may constitute a cardiometabolic risk factor through its ability to transfer cholesteryl esters from high density lipoproteins (HDL) towards apoB-containing lipoproteins(VLDL and LDL). Apolipoprotein C1 was identified earlier by this group as a potent physiological inhibitor of plasma CETP.

Our research theme :

Recently, we observed that :

  • HDL-bound apoC1 is a potent modulator of CETP activity in plasma of normolipidemic subjects.
  • Unlike HDL apoC1, VLDL apoC1 has no CETP inhibitory potential.
  • In contrast to normolipidemix humans, no relationship between plasma apoC1 and CETP activity was found in rabbits as a result of dysfunctional apoC1 in this species.

Whereas phospholipid transfer protein (PLTP) was studied initially for its implication in HDL metabolism and reverse cholesterol transport, we contributed to the demonstration of additional biological properties :

  • The regulation of the tocopherol content of lipoproteins and membranes constitutes a key function of PLTP at the intravascular and tissue sites.
  • In aortic smooth muscle cells, alpha-tocopherol, unlike gamma-tocopherol, incorporates preferentially into the shingolipid.cholesterol-enriched (lipid raft) domains and prevents 7-ketocholesterol-mediated apoptosis.
  • Human PLTP gene expression in transgenic rabbits increases plasma apoB-containing lipoproteins, reduces their antioxidative protection, and worsens diet-included atherosclerosis.
  • In two complementary mouse models of abdominal aortic aneurysm (AAA), PLTP arose a risk factor of AAA formation through its ability to worsen hypercholesterolemia at the systemic level, and to enhance inflammation at the vascular site.

As a member of the LT/LBP gene family, PLTP was found to play a prominent and pivotal role in LPS and lipid A metabolism, thus modulating inflammation and innate immunity :

  • The intravascular redistribution of aggregated LPS from the plasma lipoprotein-free fraction towards circulating lipoproteins (mainly HDL) is delayed in PLTP-deficient mice, resulting in a prolongated residence time, a higher toxicity of LPS aggregates, and a significant increase in LPS-induced mortality as compared to wild-type mice.
  • Similarly to aggregated LPS, a triacyl lipid A derivative (OM-174) readily associates with HDL when active PLTP is expressed. However, unlike for hexaacyl LPS, the PLTP-mediated association of triacyl lipid A with circulating lipoproteins extended its residence time in plasma, and magnified its proinflammatory and anti-cancer properties.

Both CETP and PLTP are target genes for LXR, and we observed that CETP expression in mice increases cholesterol biliary excretion after treatment with a pharmacological LXR agonist. We also observed that the LXR-mediated inductions of human CETP and PLTP expression are switched during the monocyte-to-macrophage differentiation, and are magnified by lipid loading. However, and unlike for PLTP, LXR-mediated upregulation of CETP expression is selectively lost in inflammatory macrophages.

By using a transcriptomic approach, our group recently identified the nuclear receptor RARα as new LXR target in macrophages, and the LXR/RARα pathway is able to stimulate macrophages efferocytosis.

Beside bile acid metabolism, CAR and PXR are able to modulate plasma cholesterol transport and lipoprotein metabolism. We observed that activation of PXR antagonizes the effects of bile acids on HDL in mice fed 1% cholic acid containing diet. We demonstrated that administration of a CAR agonist in normolipidic wild-type and HuAITg mice produces rapid and transient decreases in plasma HDL cholesterol and apoA1 levels.

Recently, we have shown that treatment of Ldlr-/- mice with a specific CAR agonist for two months is significantly reduced plasma cholesterol concentration and inhibited the development of atherosclerotic lesions in aortic valves. The decrease in plasma cholesterol was associated with a marked increase in the VLDL receptor gene expression in the liver and with faster elimination of HDL cholesterol via its conversion into bile acids.

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

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 Délégation régionale à la recherche et à la technologie 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