Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes.
Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes.
复制标题
DOI：
10.1002/hep.25702
复制
发表时间：
2012-08
期刊：
影响因子：
13.5
通讯作者：
Ji, Cheng
中科院分区：
文献类型：
--
作者：
Kao, Eddy;Shinohara, Masao;Feng, Min;Lau, Mo Yin;Ji, Cheng
A portion of HIV-infected patients under therapy with protease inhibitors (HIV PIs) concomitantly consume or abuse alcohol leading to hepatic injury. The underling mechanisms are not known. We hypothesize that HIV PI aggravates alcohol-induced liver injury through an endoplasmic reticulum (ER) stress mechanism. To address this, we treated mice and primary mouse and human hepatocytes (PMH and PHH respectively) with alcohol and the two HIV PIs: ritonavir and lopinavir. In mice, ritonavir and lopinavir (15 mg/kg body weight each) induced mild ER stress and inhibition of Sarco/ER Calcium-ATPase (SERCA) without significant increase in serum ALT levels. However, a single dose of alcohol by gavage (5g/kg body weight) plus the two HIV PIs caused a greater than 5-fold increase in serum ALT, a synergistic increase in alcohol-induced liver lipid accumulation and ER stress response, and a decrease of SERCA. Mice treated with chronic HIV PIs and alcohol developed moderate liver fibrosis. In PMH, the HIV drugs plus alcohol also inhibited SERCA expression and increased expression of GRP78, CHOP, SREBP1c and phosphorylated JNK2, which were accompanied by a synergistic increase in cell death compared to alcohol or the HIV drugs alone. In PHH, ritonavir and lopinavir or alcohol alone treatment increased mRNA of spliced Xbp1 and decreased SERCA, which were accompanied by reduced levels of intracellular calcium. Alcohol combined with the HIV drugs significantly reduced intracellular calcium levels and potentiated cell death, which was comparable to the cell death caused by the SERCA inhibitor-thapsigargin. Our findings suggest the possibility that HIV PIs potentiate alcohol-induced ER stress and injury through modulation of SERCA and maintaining calcium homeostasis should be a therapeutic aim for a better care of HIV patients.
登录
查看更多内容
影响因子：
4.4
作者：
Galligan, James J.;Fritz, Kristofer S.;Petersen, Dennis R.
通讯作者：
Petersen, Dennis R.
DOI：
10.1111/j.1440-1746.2006.04575.x
发表时间：
2006-10-01
影响因子：
4.1
作者：
Lu, Shelly C.;Martinez-Chantar, M. Luz;Mato, Jose M.
通讯作者：
Mato, Jose M.
影响因子：
15.9
作者：
Dressman, J;Kincer, J;Smart, EJ
通讯作者：
Smart, EJ
DOI：
10.1097/01.alc.0000169265.36440.ee
发表时间：
2005-06-01
影响因子：
3.2
作者：
Blasco, C;Caballería, J;Rodés, J
通讯作者：
Rodés, J
DOI：
10.1111/j.1530-0277.2011.01602.x
发表时间：
2012-01
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Howarth DL;Vacaru AM;Tsedensodnom O;Mormone E;Nieto N;Costantini LM;Snapp EL;Sadler KC
通讯作者：
Sadler KC