HIV protease inhibitors (HIV PIs) are used in the highly ctive antiretroviral therapy (HAART). However, HIV PIs are often associated with development of liver damages. The mechanisms of the HIV protease inhibitor- induced liver injury are poorly defined. Emerging evidence indicates that the HIV PIs induce endoplasmic reticulum (ER) stress response which has been shown to play an essential role in liver dysfunction including necroinflammation, hepatic cell death and fatty liver. We previously observed that alcohol consumption, which is a well-recognized co-factor in susceptibility to the infection and progression of HIV, induced hyperhomocysteinemia and ER stress response in the liver. A significant proportion of HIV infected patients abuse alcohol and it is logical to consider that an interplay between the effects of alcohol and HIV PIs contributes to severe hepatic steatosis and injury. We hypothesize that HIV PI and alcohol exert a potentiated effect on ER stress and lipid metabolism which worsens liver injury. We propose to explore the HIV PI-induced ER stress response in both primary mouse and human hepatocytes and to investigate in vivo its interactions with pathogenic effects of alcohol in animals fed alcohol.
Our specific aims are: (1) to compare ER stress and hepatic injury induced by single or combined HIV PI treatments in vivo in chronic pair- and alcohol-fed mice, and to assess additive or synergistic effects by examining HIV PI-induced ER stress response in vitro in both primary mouse and human hepatocytes and by monitoring bioavailability of HIV PIs in plasma and culture medium of hepatocytes;(2) to confirm ER stress response in mice fed orally a high methionine low folate diet in the presence or absence of single or combined HIV PIs that mimic the antiretroviral therapy in human;(3) to study synergistic mechanisms of ER stress response by HIV PIs and by alcohol through monitoring calcium releasing into the cytosol in primary mouse and human hepatocytes and through examining proteasome activities and expression and activities of glucose transporters in hepatocytes administered HIV PIs;(4) to isolate non-parenchymal cells (hepatic stellate cells, Kupffer cells, and endothelial cells) and differentiate HIV PI- or alcohol-induced ER stress response in these cell types;(5) to determine in vitro and in vivo the effectiveness of protective molecular chaperones (e.g. 4-phenylbutyrate ) in HIV PI- induced ER stress and liver injury. This project will provide a better understanding of the hepatotoxicity of HIV protease inhibitors and better strategies to improve care for HIV-infected patients.

Public Health Relevance

HIV protease inhibitors (HIV PIs) used in highly active effective ntiretroviral therapies (HAART) induce liver damages in patients with HIV/AIDS, especially in the patients who consume alcohol. We have identified that either alcohol or HIV PIs induce endoplasmic reticulum (ER) stress that plays an important role in a variety of disorders including insulin resistance, obesity, and liver disease. Understanding of additive/synergistic effects of HIV PIs and alcohol on the ER stress that worsens liver injury will provide better strategies to improve care for HIV-infected patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018612-04
Application #
8452000
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wang, Joe
Project Start
2010-04-20
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$343,934
Indirect Cost
$131,629
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zhang, Huiying; Lv, Minli; Zhao, Zhongfu et al. (2014) Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome. Gene 545:156-62
Zhang, Huiying; Lv, Minli; Jia, Jiantao et al. (2014) Expression of the 78 kD glucose-regulated protein is induced by endoplasmic reticulum stress in the development of hepatopulmonary syndrome. Gene 537:115-9
Ji, Cheng (2014) New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases. Int J Hepatol 2014:513787
Liu, Yang; Du, Juanjuan; Yan, Ming et al. (2013) Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication. Nat Nanotechnol 8:187-92
Lau, Mo Yin; Han, Hui; Hu, Jay et al. (2013) Association of cyclin D and estrogen receptor ?36 with hepatocellular adenomas of female mice under chronic endoplasmic reticulum stress. J Gastroenterol Hepatol 28:576-83
Han, Hui; Hu, Jay; Lau, Mo Y et al. (2013) Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors. Front Genet 4:224
Than, Tin Aung; Lou, Huan; Ji, Cheng et al. (2011) Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. J Biol Chem 286:22047-54
Dara, Lily; Ji, Cheng; Kaplowitz, Neil (2011) The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 53:1752-63
Loftus, Neil; Barnes, Alan; Ashton, Simon et al. (2011) Metabonomic investigation of liver profiles of nonpolar metabolites obtained from alcohol-dosed rats and mice using high mass accuracy MSn analysis. J Proteome Res 10:705-13
Ji, Cheng; Kaplowitz, Neil; Lau, Mo Yin et al. (2011) Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54:229-39

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