CD36 deficiency aggravates macrophage infiltration and hepatic inflammation by up-regulating MCP-1 expression of hepatocytes through HDAC2-dependant pathway

AIMS: Cluster of differentiation 36 (CD36) is involved in the development of non-alcoholic steatohepatitis (NASH). Excess CD36 facilitates liver cells taking fatty acid and activates inflammatory signals to promote hepatic steatosis and inflammation. However, CD36-deficiency paradoxically promotes non-alcoholic fatty liver disease by unknown mechanisms. We explored the probable molecular mechanism of hepatic inflammation induced by CD36 deficiency. RESULTS: CD36 deletion in mice(CD36-/- mice) specifically increased MCP-1 in hepatocytes, promoted macrophage migration to liver and aggravated hepatic inflammatory response and fibrosis. The nuclear expression of histone deacetylase 2 (HDAC2) which highly expresses in wild-type hepatocytes and has an inhibitory effect on acetyl H3 was reduced in CD36 deficiency hepatocytes. Consequently, the level of acetyl H3 binding to MCP-1 promoters was increased in CD36 deficient hepatocytes, causing hepatic specific MCP-1 transcriptional activation. Reduction of nuclear HDAC2 in both CD36-/- mice liver and cultured hepatocytes was due to reduction of intracellular reactive oxygen species (ROS) level, while supplement of low concentration hydrogen peroxide (H2O2) overcame the suppression of HDAC2 caused by CD36 deficiency, decreasing MCP-1 gene transcription and microphage migration. INNOVATION: Our results provide first evidence that decreased ROS production by CD36 deletion was also harmful for livers. The fine balance of CD36 plays an important role in maintaining balances of hepatic ROS and nuclear HDAC2 which could be potential new therapeutic strategy for the prevention of NASH development. CONCLUSION: CD36 deficiency promoted the development of NASH by facilitating transcription of MCP-1 in hepatocytes, due to the reduction of ROS and nuclear HDAC2.