Altered hepatic expression of SREBP-1 and PPARγ is associated with liver injury in insulin-resistant lipodystrophic HIV-infected patients

Publisher Website
Google Scholar
Abstract
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 (PPARα, PPARγ1/PPARγ2) 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 PPARγ1 (P = 0.03, P = 0.05 and P = 0.01) and PPARγ2 (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 PPARγ1 and PPARγ2 expression (r = −0.57, P = 0.03 and r = −0.6, P = 0.02, respectively). Conclusion: Insulin-resistant lipodystrophic HIV-infected patients may develop NASH. Steatosis is associated with overexpression of SREBP-1 and fibrosis with decreased expression of PPARγ1 and PPARγ2. These results suggest that altered expression of SREBP-1 and PPARγ could contribute to the pathogenesis of steatosis and fibronecrotic changes in insulin-resistant lipodystrophic patients.