Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection.

ABSTRACT

BACKGROUND: Entecavir and tenofovir-disoproxil-fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. METHODS: A retrospective study was performed on HBV patients administered entecavir or tenofovir-disoproxil-fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6-12 months after treatment initiation, were analyzed. A 11 propensity score matching was applied to the assignment of tenofovir-disoproxil-fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. RESULTS: Administration of tenofovir-disoproxil-fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir-disoproxil-fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir-disoproxil-fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir-disoproxil-fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir-disoproxil-fumarate on CD36. CONCLUSIONS: Tenofovir-disoproxil-fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.