Altered hepatic expression of SREBP-1 and PPARgamma is associated with liver injury in insulin-resistant lipodystrophic HIV-infected patients.
BACKGROUND
HIV-infected patients with HAART-related lipodystrophy are frequently insulin resistant and at risk of non-alcoholic fatty liver disease (NAFLD) with steatohepatitis (NASH). The transcription factors, peroxisome proliferator activated receptors (PPARalpha, PPARgamma1/PPARgamma2) and sterol regulatory element binding proteins (SREBP-1) regulate liver lipid metabolism. Here, we examined whether their expression was modified and related to liver injury in HIV-infected patients.


METHODS
Fourteen HAART-treated HIV patients (nine with and five without insulin resistance) who had liver biopsy because of unexplained elevated transaminases were compared with nine non-HIV age-and body mass index-matched patients with NAFLD and 10 controls without steatosis. Hepatic expression of PPARs and SREBP-1 was assessed by real time reverse transcriptase-polymerase chain reaction.


RESULTS
Liver histology showed NASH in six of nine insulin-resistant lipodystrophic and two of five non-insulin-resistant HIV patients. Compared with NAFLD or control subjects, expression of SREBP-1 was significantly higher only in HIV-insulin-resistant patients (P = 0.04 and P = 0.02) whereas, compared to controls, HIV-insulin-resistant, HIV-non-insulin-resistant and NAFLD patients had lower expressions of PPARgamma1 (P = 0.03, P = 0.05 and P = 0.01) and PPARgamma2 (P = 0.04, P = 0.05 and P = 0.01). Among HIV patients, the percentage of steatosis was positively correlated with SREBP-1 expression (r = 0.62, P = 0.04) whereas the score of fibrosis was inversely correlated with PPARgamma1 and PPARgamma2 expression (r = -0.57, P = 0.03 and r = -0.6, P = 0.02, respectively).


CONCLUSIONS
Insulin-resistant lipodystrophic HIV-infected patients may develop NASH. Steatosis is associated with overexpression of SREBP-1 and fibrosis with decreased expression of PPARgamma1 and PPARgamma2. These results suggest that altered expression of SREBP-1 and PPARgamma could contribute to the pathogenesis of steatosis and fibronecrotic changes in insulin-resistant lipodystrophic patients.
Lemoine
Maud
M
Université Pierre et Marie Curie, Faculté de Médecine, Paris, F-75012 France.
Barbu
Véronique
V
Girard
Pierre Marie
PM
Kim
Minji
M
Bastard
Jean-Philippe
JP
Wendum
Dominique
D
Paye
François
F
Housset
Chantal
C
Capeau
Jacqueline
J
Serfaty
Lawrence
L
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D005234:Fatty Liver / Q000378:metabolism / Q000821:virology*; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
D047495:PPAR gamma; D051780:Sterol Regulatory Element Binding Protein 1