Metabolic dysregulation in the Atp7b -/- Wilson's disease mouse model

Authors: WOOTON-KEE, CLAVIA RUTH - BAYLOR COLLEGE OF MEDICINE; ROBERTSON, MATTHEW - BAYLOR COLLEGE OF MEDICINE; ZHOU, YING - BAYLOR COLLEGE OF MEDICINE; DONG, BINGNING - BAYLOR COLLEGE OF MEDICINE; SUN, ZHEN - BAYLOR COLLEGE OF MEDICINE; KIM, KANG HO - BAYLOR COLLEGE OF MEDICINE; LIU, HAILAN - BAYLOR COLLEGE OF MEDICINE; XU, YONG - BAYLOR COLLEGE OF MEDICINE; PUTLURI, NAGIREDDY - BAYLOR COLLEGE OF MEDICINE; SAHA, PRADIP - BAYLOR COLLEGE OF MEDICINE; COARFA, CHRISTIAN - BAYLOR COLLEGE OF MEDICINE; MOORE, DAVID - BAYLOR COLLEGE OF MEDICINE; NUOTIO-ANTAR, ALLI - BAYLOR COLLEGE OF MEDICINE

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/23/2019
Publication Date: 1/28/2020
Citation: Wooton-Kee, C., Robertson, M., Zhou, Y., Dong, B., Sun, Z., Kim, K., Liu, H., Xu, Y., Putluri, N., Saha, P., Coarfa, C., Moore, D.D., Nuotio-Antar, A.M. 2020. Metabolic dysregulation in the Atp7b -/- Wilson's disease mouse model. Proceedings of the National Academy of Sciences. 117(4):2076–2083.

Interpretive Summary: Atp7b is a copper transporter that is inactivated in Wilson's disease patients. Although it is normally abundant in liver, not much is known about effects of reduced Atp7b activity on metabolism. We found that Atp7b deficiency in mice resulted in blunted weight gain, associated with reduced food intake and increased physical activity, as well as increased insulin sensitivity. However, Atp7b deficiency also resulted in defective glucose production by the liver, making these mice more susceptible to hypoglycemia when fasting. Taken together, our results suggest that, although somewhat protected from obesity and type 2 diabetes, even when fed a high fat, high sucrose "Western"-type diet, untreated Wilson's disease patients may have aberrant regulation of blood glucose levels, in particular when fasting, with a tendency toward hypoglycemia.

Technical Abstract: Inactivating mutations in the copper transporter Atp7b result in Wilson's disease. The Atp7b-/- mouse develops hallmarks of Wilson's disease. The activity of several nuclear receptors decreased in Atp7b-/- mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b-/- mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography-mass spectrometry and correlated with transcriptomic data. Atp7b-/- mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b-/- mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b-/- mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b-/- mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b-/- mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b-/- mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b-/- mice.