Cluster of Differentiation 36 Deficiency Aggravates Macrophage Infiltration and HepaticInflammation by Upregulating Monocyte Chemotactic Protein-1 Expression of HepatocytesThrough Histone Deacetylase 2-Dependent Pathway

Zhong S1, Zhao L1, Wang Y1, Zhang C1, Liu J1, Wang P1, Zhou W1, Yang P1, Varghese Z2, Moorhead JF2, Chen Y1, Ruan XZ1,2,3,4.

Antioxid Redox Signal. 2017 Aug 1;27(4):201-214. doi: 10.1089/ars.2016.6808. Epub 2017 Jan 10.

PMID:27967209                       DOI:10.1089/ars.2016.6808

Abstract

AIMS:

Cluster of differentiation 36 (CD36) is involved in the development of nonalcoholic steatohepatitis (NASH). Excess CD36 facilitates liver cells taking fatty acid and activates inflammatory signals to promote hepatic steatosis and inflammation. However, CD36deficiency paradoxically promotes nonalcoholic 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 monocyte chemotactic protein-1 (MCP-1) in hepatocytes, promoted macrophage migration to the liver, and aggravated hepatic inflammatory response and fibrosis. The nuclear expression ofhistone deacetylase 2 (HDAC2), which highly expresses in wild-type hepatocytes and has an inhibitory effect on acetyl histone 3 (H3), was reduced in CD36-deficient 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 a potential new therapeutic strategy for the prevention of NASH development.

CONCLUSION:

CD36 deficiency promoted the development of NASH by facilitating the transcription of MCP-1 in hepatocytes due to the reduction of ROS and nuclear HDAC2. Antioxid. Redox Signal. 00, 000-000.