Objective-Plasma phospholipid transfer protein (PLTP) is involved in intravascular lipoprotein metabolism. PLTP is known to act through 2 main mechanisms: by remodeling high-density lipoproteins (HDL) and by increasing apolipoprotein (apo) B-containing lipoproteins. The aim of this study was to generate a new model of human PLTP transgenic (HuPLTPTg) rabbit and to determine whether PLTP expression modulates atherosclerosis in this species that, unlike humans and mice, displays naturally very low PLTP activity. Methods and Results-In HuPLTPTg rabbits, the human PLTP cDNA was placed under the control of the human eF1-␣ gene promoter, resulting in a widespread tissue expression pattern and in increased plasma PLTP. The HuPLTPTg rabbits showed a significant increase in the cholesterol content of the plasma apoB-containing lipoprotein fractions, with a more severe trait when animals were fed a cholesterol-rich diet. In contrast, HDL cholesterol level was not modified in HuPLTPTg rabbits. Formation of aortic fatty streaks was increased in hypercholesterolemic HuPLTPTg animals as compared with nontransgenic littermates. Key Words: atherosclerosis Ⅲ lipoproteins Ⅲ metabolism Ⅲ transgenic models H uman plasma contains 2 distinct lipid transfer proteins (cholesteryl ester transfer protein [CETP] and phospholipid transfer protein [PLTP]) that promote the rapid exchange of lipid species between circulating lipoproteins, as well as between circulating lipoproteins and cells. 1 Although most reported data agree that the putative implication of CETP in lipoprotein metabolism and atherosclerotic process mostly concerns the net transfer of cholesteryl esters from antiatherogenic high-density lipoproteins (HDL) to potentially atherogenic apolipoprotein (apo) B-containing lipoproteins, 1 the precise function of PLTP and its consequences in terms of atherogenesis remain a matter of debate. PLTP was identified initially for its ability to promote the transfer of phospholipids from triglyceride-rich lipoproteins to HDL in the postprandial phase. 2 Subsequent studies reported that PLTP is also a key player in the HDL conversion process, leading to the emergence of large and small HDL products. 3,4 Recently, PLTP in human plasma was shown to reside mainly on lipid-poor complexes in association with proteins linked to immunity and inflammation, suggesting that the biological function of PLTP is rather complex in nature. 5 In support of this view, PLTP expression in the mouse was found to increase the production of apoB-containing lipoproteins by the liver 6 and intestine, 7 to decrease very low density lipoprotein (VLDL) catabolism, 8 to reduce the antioxidant protection of atherogenic lipoproteins, 9,10 to trigger inflammation, 11 and to promote the association of lipopolysaccharides with circulating lipoproteins. 12 All these properties have long been shown to influence the atherosclerotic process, whether acting individually or in a combined manner. Conclusion-HumanHigh plasma PLTP concentrations were earlier reported in diabetic...

The molecular composition of a core conduction element formed by the alpha-subunit of cloned epithelial Na+ channels (ENaC) was studied in planar lipid bilayers. Two pairs of in vitro translated proteins were employed in combinatorial experiments: 1) wild-type (WT) and an N-terminally truncated alphaDeltaN-rENaC that displays accelerated kinetics (tauo = 32 +/- 13 ms, tauc = 42 +/- 11 ms), as compared with the WT channel (tauc1 = 18 +/- 8 ms, tauc2 = 252 +/- 31 ms, and tauo = 157 +/- 43 ms); and 2) WT and an amiloride binding mutant, alphaDelta278-283-rENaC. The channels that formed in a alphaWT:alphaDeltaN mixture fell into two groups: one with tauo and tauc that corresponded to those exhibited by the alphaDeltaN-rENaC alone, and another with a double-exponentially distributed closed time and a single-exponentially distributed open time that corresponded to the alphaWT-rENaC alone. Five channel subtypes with distinct sensitivities to amiloride were found in a 1alphaWT:1alphaDelta278-283 protein mixture. Statistical analyses of the distributions of channel phenotypes observed for either set of the WT:mutant combinations suggest a tetrameric organization of alpha-subunits as a minimal model for the core conduction element in ENaCs.

Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis.

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