Journal
CELL METABOLISM
Volume 29, Issue 1, Pages 174-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.08.020
Keywords
-
Categories
Funding
- National Cancer Institute [T32 CA071345, K01 CA140861]
- Uehara Memorial Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases [DK099558]
- European Union [ERC-2014-AdG-671231 HEPCIR]
- Irma T. Hirschl Trust
- U.S. Department of Defense [W81XWH-16-1-0363]
- Canadian Cancer Society Research and Innovation Fund
- Canadian Institutes of Health Research [125980-1,, 144625-1]
- Nimbus Therapeutics
- Gilead Sciences
- Canadian Liver Foundation
- Canada Research Chair
- J. Bruce Duncan Chair in Metabolic Diseases
Ask authors/readers for more resources
The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available