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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #285068
Title: Inflammation modulates human HDL composition and function in vivo

Author
item DE LA LLERA MOYA, MARGARITA - Children'S Hospital - Philadelphia, Pennsylvania
item MCGILLICUDDY, FIONA C. - University College Dublin
item HINKLE, CHRISTINE C. - University Of Pennsylvania
item BYRNE, MICHAEL - University Of Pennsylvania
item JOSHI, MICHELLE R. - Children'S Hospital - Philadelphia, Pennsylvania
item NGUYEN, VIHN - Children'S Hospital - Philadelphia, Pennsylvania
item TABITA-MARTINEZ, JENNIFER - University Of Pennsylvania
item WOLFE, MEGAN L. - University Of Pennsylvania
item BADELLINO, KAREN - University Of Pennsylvania
item PRUSCINO, LETICIA - University Of Pennsylvania
item MEHTA, NEHAL N. - University Of Pennsylvania
item ASZTALOS, BETA F. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item REILLY, MUREDACH P. - University Of Pennsylvania

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/21/2012
Publication Date: 6/1/2012
Citation: De La Llera Moya, M., Mcgillicuddy, F., Hinkle, C., Byrne, M., Joshi, M., Nguyen, V., Tabita-Martinez, J., Wolfe, M., Badellino, K., Pruscino, L., Mehta, N., Asztalos, B., Reilly, M. 2012. Inflammation modulates human HDL composition and function in vivo. Atherosclerosis. 222(2):390-394.

Interpretive Summary: Reverse cholesterol transport (RCT) is considered a major function of high density lipoprotein (HDL)in keeping fatty deposits from forming on artery walls. Loss of HDL RCT functions may contribute to the buildup of these deposits in chronic inflammatory states including obesity and insulin resistance. Inflammation may directly impair HDL function and RCT, but limited data support this concept in humans. To address this possibility, we used low-dose human endotoxemia (blood poisoning due to bacterial cell decomposition) to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Our data demonstrate that human endotoxemia remodels HDL with a characteristic decrease in lipid-poor pre- beta-1 and other small and medium sized HDL particles. It also induces sPLA2-IIA in the blood and suppresses CETP mass and LCAT activity, biochemical consequences known to remodel HDL phospholipid and cholesterol. Endotoxemia also reduced HDL capacity to expel cholesterol from SR-BI and ABCA1, but not ABCG1, model systems. Furthermore, our data suggest that global measures such as HDL-C or apoA-I likely fail to capture functionality that may reside in HDL sub-fractions.

Technical Abstract: Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans. Our study was designed to investigate this relationship. We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-Beta1a HDL particles determined by 2-D gel electrophoresis (-32.2 +/- 9.3% at 24 h, p less than 0.05) as well as small (-23.0 +/- 5.1%,p less than 0.01, at 24 h) and medium (-57.6 +/- 8.0% at 16 h, p less than 0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (approximately 36 fold increase) and suppression of lecithin: cholesterol acyltransferase activity (-20.8 +/- 3.4% at 24 h, p less than 0.01) and cholesterol ester transfer protein mass (-22.2 +/- 6.8% at 24 h, p less than 0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models. Although epidemiological studies suggest an inverse relation between circulating HDL-C and cardiovascular disease (CVD), it remains unclear whether low HDL-C is causative. However, HDL is the most complex lipoprotein family and its function and metabolism are not well understood as of yet. Our study provides novel data demonstrating that inflammation in humans modulates HDL composition and function in the absence of substantial change in HDL-C or apoA-I thereby reinforcing the concept that alternative measures of HDL function need to be applied in order to address whether HDL is causally involved in atherosclerosis.