Steatohepatitis/Metabolic Liver Disease
Article first published online: 30 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 2, pages 509–521, August 2011
How to Cite
Qiao, A., Liang, J., Ke, Y., Li, C., Cui, Y., Shen, L., Zhang, H., Cui, A., Liu, X., Liu, C., Chen, Y., Zhu, Y., Guan, Y., Fang, F. and Chang, Y. (2011), Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis. Hepatology, 54: 509–521. doi: 10.1002/hep.24402
Potential conflict of interest: Nothing to report.
This work was supported by the Major State Basic Research Development Program of China (973 program grant 2011CB504004) and the National Natural Science Foundation of China (grants 30971079, 30800389, and 90919019).
- Issue published online: 25 JUL 2011
- Article first published online: 30 JUN 2011
- Accepted manuscript online: 5 MAY 2011 10:49AM EST
- Manuscript Accepted: 20 APR 2011
- Manuscript Received: 7 JAN 2011
Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1c mediated the insulin and liver X receptor agonist TO901317-dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased the serum triglyceride level and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance. Conclusion: Our data suggest that mouse PNPLA3, which is a lipogenic gene directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism. (HEPATOLOGY 2011;)