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

• Published in: AIDS (London) Vol. 20; no. 3; pp. 387 - 395
• Main Authors: Lemoine, Maud, Barbu, Véronique, Girard, Pierre Marie, Kim, Minji, Bastard, Jean-Philippe, Wendum, Dominique, Paye, François, Housset, Chantal, Capeau, Jacqueline, Serfaty, Lawrence
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14.02.2006; Wolters Kluwer
• Subjects: Biological and medical sciences; Dermatology; Drug toxicity and drugs side effects treatment; Human immunodeficiency virus; Human viral diseases; Infectious diseases; Life Sciences; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Pharmacology. Drug treatments; Skin involvement in other diseases. Miscellaneous. General aspects; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Immunopathology; Skin disease; transcription factors; Liver; lipid metabolism; Lipids; AIDS; Metabolism; Immune deficiency; Insulin; Steatosis; Infection; Target tissue resistance; Viral disease; Lipodystrophy; Adipose tissue disorders; Transcription factor; insulin resistance
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/01.aids.0000206503.01536.11

HIV-infected patients with HAART-related lipodystrophy are frequently insulin resistant and at risk of non-alcoholic fatty liver disease (NAFLD) with steato-hepatitis (NASH). The transcription factors, peroxisome proliferator activated receptors (PPAR alpha , PPAR gamma 1/PPAR gamma 2) 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. 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.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-noninsulin-resistant and NAFLD patients had lower expressions of PPAR gamma 1 (P = 0.03, P = 0.05 and P = 0.01) and PPAR gamma 2 (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 PPAR gamma 1 and PPAR gamma 2 expression (r = -0.57, P = 0.03 and r = -0.6, P = 0.02, respectively). Insulin-resistant lipodystrophic HIV-infected patients may develop NASH. Steatosis is associated with overexpression of SREBP-1 and fibrosis with decreased expression of PPAR gamma 1 and PPAR gamma 2. These results suggest that altered expression of SREBP-1 and PPAR gamma could contribute to the pathogenesis of steatosis and fibronecrotic changes in insulin-resistant lipodystrophic patients.