%0 Journal Article
%T Hepatocyte-specific loss of DDB1 attenuates hepatic steatosis but aggravates liver inflammation and fibrosis in MASH.
%A Gu Q
%A Chang Y
%A Jin Y
%A Fang J
%A Ji T
%A Lin J
%A Zhu X
%A Dong B
%A Ying H
%A Fan X
%A Li Z
%A Gao Z
%A Zhu Y
%A Tong Y
%A Cai X
%J Hepatol Commun
%V 8
%N 7
%D 2024 Jul 1
%M 38934719
%F 5.701
%R 10.1097/HC9.0000000000000474
%X <B>BACKGROUND: </B>MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its pathogenesis. Damaged DNA binding protein 1 (DDB1) participates in lipid metabolism. Nevertheless, the function of DDB1 in MASH is unclear.<BR><B>METHODS: </B>Clinical liver samples were obtained from patients with MASH and control individuals by liver biopsy. Hepatocyte-specific Ddb1-knockout mice and liver Hmgb1 knockdown mice were fed with a methionine-and choline-deficient diet to induce MASH.<BR><B>RESULTS: </B>We found that the expression of DDB1 in the liver was significantly decreased in MASH models. Hepatocyte-specific ablation of DDB1 markedly alleviated methionine-and choline-deficient diet-induced liver steatosis but unexpectedly exacerbated inflammation and fibrosis. Mechanistically, DDB1 deficiency attenuated hepatic steatosis by downregulating the expression of lipid synthesis and uptake genes. We identified high-mobility group box 1 as a key candidate target for DDB1-mediated liver injury. DDB1 deficiency upregulated the expression and extracellular release of high-mobility group box 1, which further increased macrophage infiltration and activated HSCs, ultimately leading to the exacerbation of liver inflammation and fibrosis.<BR><B>CONCLUSIONS: </B>These data demonstrate the independent regulation of hepatic steatosis and injury in MASH. These findings have considerable clinical implications for the development of therapeutic strategies for MASH.