Under normal physiological conditions, high density lipoprotein (HDL) plays an important role in regulating cellular cholesterol homeostasis and also possesses anti-inflammatory properties. Beneficial properties of HDL have been ascribed, in large part, to apolipoprotein A-I (apoA-I). Inflammation, however, can convert HDL into a dysfunctional lipoprotein particle that is depleted of apoA-I and enriched with acute phase proteins. Therapeutic approaches that increase plasma levels of functional HDL reduce ischemia-reperfusion (I/R) injury and other inflammatory disorders. Previous studies show that apoA-I mimetic peptides exert anti-inflammatory effects by increasing functional HDL levels and inhibiting monocyte/macrophage (M?) infiltration in tissues. In this regard, it was shown that the synthetic peptide 4F, which mimics functional properties of apoA-I, alters the metabolic profile of human monocyte-derived M?s, resulting in the adoption of an anti-inflammatory M2 phenotype. These responses were associated with up-regulation of genes that regulate mitochondrial respiration, resulting in an increase in oxidative phosphorylation and ATP formation. In this application, we present data showing that 4F reduces hepatocellular injury in a murine model of hepatic I/R injury. The protective response to 4F treatment is thought to be due to an increase in circulating levels of functional HDL. Specifically, we show that Kupffer cells (KCs), tissue resident M?s, adopt an anti-inflammatory phenotype. HDL may induce this response by increasing mitochondrial respiration and ATP formation, processes that support the induction of an anti-inflammatory wound healing response. Second, HDL may improve survival in hepatocytes via induction of autophagy, resulting in the clearance of damaged mitochondria and their replacement with new functional mitochondria. A mouse model of liver I/R will be used to test these hypotheses, and underlying mechanisms will be defined in cell culture systems.

Public Health Relevance

Interruption of organ blood flow promotes inflammation and free radical injury. Functional high density lipoprotein (HDL) cholesterol has been shown to reduce tissue injury associated with impaired blood flow. This project will define mechanisms by which HDL limits organ injury associated with ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK108836-01
Application #
9077453
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Sherker, Averell H
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Giordano-Mooga, Samantha; Datta, Geeta; Wolkowicz, Paul et al. (2018) The Apolipoprotein E Mimetic Peptide AEM-2 Attenuates Mitochondrial Injury And Apoptosis In Human THP-1 Macrophages. Curr Top Pept Protein Res 19:15-25
White, C Roger; Datta, Geeta; Giordano, Samantha (2017) High-Density Lipoprotein Regulation of Mitochondrial Function. Adv Exp Med Biol 982:407-429
White, C Roger; Anantharamaiah, G M (2017) Cholesterol reduction and macrophage function: role of paraoxonases. Curr Opin Lipidol 28:397-402
White, C Roger; Giordano, Samantha; Anantharamaiah, G M (2016) High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms. Chem Phys Lipids 199:161-169