6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 25–28 October 2004 - Washington, DC, USA

STEATOHEPATITIS IS ASSOCIATED WITH INCREASED HEPATIC EXPRESSION OF SREBP-1 IN HIV-INFECTED LIPODYSTROPHIC PATIENTS

Antiviral Therapy 2004; 9(6):L12 (abstract no. 17)

M Lemoine^1,2, V Barbu^1,2, JP Bastard^2,3, D Wendum¹, M Maachi^2,3, F Paye^1,2, R Poupon^1,2, PM Girard¹, C Housset^2,3, J Capeau^2,3 and L Serfaty^1,2
1Saint-Antoine Hospital, Paris, France; ²INSERM U402, Paris, France; and ³Tenon Hospital, Paris, France

OBJECTIVES: ART-induced lipodystrophy could be associated with hepatic steatosis. However, due to the presence of insulin resistance, these patients could be at risk of steatohepatitis and liver injury. In rodents, the transcription factors PPARs and SREBP-1, controlling hepatic glucose and lipid metabolism, are probably involved in steatosis. Ritonavir increased hepatic expression of SREBP-1 and steatosis. We therefore examined liver pathological changes and expression of PPARα, PPARγ1, γ2 and SREBP-1 in HIV-infected lipodystrophic patients.

METHODS: Three groups of patients were studied. Group 1: nine HIV lipodystrophic patients (including PI in eight patients), without HBV or HCV infection, who had liver biopsy because of elevated transaminases; Group 2: nine patients with non-alcoholic fatty liver disease (NAFLD), age and BMI matched with Group 1; Group 3: 10 controls without steatosis. All patients had determination of serum fasting glucose, insulin, triglycerides, leptin and adiponectin levels. Hepatic expression of PPARs and SREBP-1 was assessed by real-time RT-PCR.

RESULTS: HIV-LD and NAFLD patients compared with controls had higher insulin (median 6.9 and 15.7 vs 2.8 mU/l, P<0.05) and lower adiponectin levels (median 5.2 and 6.4 vs 12 µg/ml, P<0.05). Liver histology in HIV-LD patients showed steatohepatitis in four out of nine cases, associated with portal fibrosis in all cases. Hepatic expression of SREBP-1 was higher in HIV-LD patients than in NAFLD or control patients (median 90 vs 50 and 40 104 copies/µg RNA, respectively, P<0.05). HIV-LD patients with steatosis had significantly higher SREBP-1 expression than those without steatosis (median 175 vs 85 104 copies/µg RNA, P<0.05). Hepatic expression of PPARα, PPARγ1, and PPARγ2 was not significantly different between the three groups.

CONCLUSION: In patients with ART-related lipodystrophy 1) steatohepatitis is frequent, 2) hepatic SREBP-1 mRNA is overexpressed as compared with NAFLD patients or with controls, 3) SREBP-1 overexpression is associated with steatosis and 4) expression of PPAR genes is not significantly modified. These results suggest that SREBP-1 contributes to the pathogenesis of fatty liver in these patients.

2004-10-25
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