Leptin replacement therapy but not dietary polyunsaturated fatty acid alleviates HIV protease inhibitor-induced dyslipidemia and lipodystrophy in mice.

Abstract

A major complication associated with the use of protease inhibitors (PIs) in treatment of HIV-infected patients is lipid abnormalities including dyslipidemia, lipodystrophy, and liver steatosis. Previous studies revealed that these abnormalities are associated with PI-induced accumulation of activated sterol regulatory element binding proteins (SREBPs) in the nucleus of liver and adipose tissues, resulting in constitutive activation of lipid metabolism genes. This study used the mouse model to determine the potential of polyunsaturated fatty acid (PUFA) diet or leptin replacement therapy to alleviate these PI-induced metabolic abnormalities. Results showed that feeding C57BL/6 mice with a PUFA-rich diet failed to normalize plasma cholesterol and triglyceride levels in ritonavir-treated mice. The PUFA-rich diet also had no effect on ritonavir-induced interscapular fat accumulation and liver steatosis. In contrast, daily administration of leptin significantly reversed the elevated plasma cholesterol level induced by ritonavir. Leptin replacement therapy also significantly reduced the ritonavir-induced interscapular fat mass and improved liver steatosis. Taken together, these data suggest that PI-induced lipid abnormalities, especially dyslipidemia, lipodystrophy, and liver steatosis, may be reduced with leptin replacement therapy.