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

Abigael Muchenditsi, Haojun Yang, James P. Hamilton, Lahari Koganti, Franck Housseau, Lisa Aronov, Hongni Fan, Hannah Pierson, Ashima Bhattacharjee, Robert Murphy, Cynthia Sears, James Potter, Clavia R. Wooton-Kee, Svetlana Lutsenko

Research output: Contribution to journalArticlepeer-review

Abstract

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 H ep 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 H ep livers than in Atp7b -/- mice, suggesting better sequestration of excess copper. Characterization of purified cell populations also revealed that nonparenchymal cells in Atp7b H ep 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 H ep 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.

Original languageEnglish (US)
Pages (from-to)G39-G49
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume313
Issue number1
DOIs
StatePublished - 2017

Keywords

  • Copper
  • Copper-transporting ATPase 2
  • Hepatocytes
  • Obesity
  • Wilson disease

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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