Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silenced during metabolic disorders and liver cancer. We generated an hepatocyte-specific TIMP3 ‘gain-of-function’ mouse model under the control of the Albumin promoter (AlbT3) and investigated its effects during high-fat diet (HFD). After 16 weeks of HFD, TIMP3 overexpression significantly improved glucose metabolism, hepatic fatty acid oxidation and cholesterol homeostasis. In AlbT3 mice CYP7A1, MDR3 and MRP2 gene expressions were observed, consistent with higher bile acid synthesis and export. Next, to evaluate the role of A Disintegrin and Metalloproteinase 17 (ADAM17), a crucial target of TIMP3, in these processes, we created mice deficient in Adam17 specifically in hepatocyte (A17LKO) or in myeloid lineage (A17MKO), founding that only A17LKO showed improvement in liver steatosis induced by HFD. Moreover, both, AlbT3 and A17LKO significantly reduced diethylnitrosamine-initiated, HFD-promoted hepatic tumorigenesis assessed by tumor multiplicity and total tumor area. Taken together, these data indicate that hepatic TIMP3 can slow progression of NAFLD, and tumorigenesis, at least in part, through the regulation of ADAM17 activity.

Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice

“…Timp3, the main natural regulator of TACE (TNF-α-converting enzyme) activity [ 26 ], is a crucial regulator in inflammation, fibrosis and progression of NAFLD and HCC [ [27] , [28] , [29] ]. Mice lacking Timp3 result in liver inflammation caused by increased TNF-α activity and defective response to liver injury [ 27 ].…”

“…Mice lacking Timp3 result in liver inflammation caused by increased TNF-α activity and defective response to liver injury [ 27 ]. Hepatocyte-specific overexpression of Timp3 could prevents NAFLD and tumorigenesis through the regulation of ADAM17 activity [ 28 ]. Macrophage-specific overexpression of Timp3 could protects from insulin resistance, NASH and metabolic inflammation in mice [ 29 ].…”

MicroRNA 221/222 cluster kicks out Timp-3 to inflame the liver

“…In this issue of EBioMedicine Yanan Cao and coworkers describe an intriguing cross-talk between microRNA 221/222 and TIMP3 [ 2 ], an inhibitor of metalloproteinase previously involved in hepatic inflammation and steatosis [ 3 , 4 ].…”

“Single-nucleus RNA-seq2 reveals a functional crosstalk between liver zonation and ploidy”

“…Recently, changes in the expression patterns of transcriptional regulators and downstream target genes have been associated with the development and progression of chronic liver diseases such as NAFLD [65,66], non-alcoholic steatohepatitis (NASH) [67], fibrosis [15] and human hepatocellular carcinoma (HCC) [54]. Here we show that our methodology is highly sensitive to detect those gene markers in the nuclear transcriptome ( Fig.…”