Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice

Copper-transporting ATPase 2 (ATP7B) is essential for mammalian copper homeostasis. Mutations in ATP7B result in copper accumulation, especially in the liver, and cause Wilson disease (WD). The major role of hepatocytes in WD pathology is firmly established. It is less certain whether the excess Cu in hepatocytes is solely responsible for development of WD. To address this issue, we generated a mouse strain for Cre-mediated deletion of Atp7b and inactivated Atp7b selectively in hepatocytes. Atp7b^Hep mice accumulate copper in the liver, have elevated urinary copper, and lack holoceruloplasmin but show no liver disease for up to 30 wk. Liver inflammation is muted and markedly delayed compared with the age-matched Atp7b^–/– null mice, which show a strong type1 inflammatory response. Expression of metallothioneins is higher in Atp7b^Hep livers than in Atp7b^–/– mice, suggesting better sequestration of excess copper. Characterization of purified cell populations also revealed that nonparenchymal cells in Atp7b^Hep liver maintain Atp7b expression, have normal copper balance, and remain largely quiescent. The lack of inflammation unmasked metabolic consequences of copper misbalance in hepatocytes. Atp7b^Hep animals weigh more than controls and have higher levels of liver triglycerides and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. By 45 wk, all animals develop liver steatosis on a regular diet. Thus copper misbalance in hepatocytes dysregulates lipid metabolism, whereas development of inflammatory response in WD may depend on copper status of nonparenchymal cells. The implications of these findings for the cell-targeting WD therapies are discussed.

NEW & NOTEWORTHY Targeted inactivation of copper-transporting ATPase 2 (Atp7b) in hepatocytes causes steatosis in the absence of inflammation.

From: Muchenditsi, A., Yang, H., Hamilton, J. P., Koganti, L., Housseau, F., Aronov, L., Fan, H., Pierson, H., Bhattacharjee, A., Murphy, R., Sears, C., Potter, J., Wooton-Kee, C. R., Lutsenko, S. http://ajpgi.physiology.org/cgi/content/abstract/313/1/G39?rss=1