Skip to main content

Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis.

Publication ,  Journal Article
Chandrashekaran, V; Das, S; Seth, RK; Dattaroy, D; Alhasson, F; Michelotti, G; Nagarkatti, M; Nagarkatti, P; Diehl, AM; Chatterjee, S
Published in: Biochim Biophys Acta
January 2016

Metabolic oxidative stress via CYP2E1 can act as a second hit in NASH progression. Our previous studies have shown that oxidative stress in NASH causes higher leptin levels and induces purinergic receptor X7 (P2X7r). We tested the hypothesis that higher circulating leptin due to CYP2E1-mediated oxidative stress induces P2X7r. P2X7r in turn activates stellate cells and causes increased proliferation via modulating Glut4, the glucose transporter, and increased intracellular glucose. Using a high fat diet-fed NAFLD model where bromodichloromethane (BDCM) was administered to induce CYP2E1-mediated oxidative stress, we show that P2X7r expression and protein levels were leptin and CYP2E1 dependent. P2X7r KO mice had significantly decreased stellate cell proliferation. Human NASH livers showed marked increase in P2X7r, and Glut4 in α-SMA positive cells. NASH livers had significant increase in Glut4 protein and phosphorylated AKT, needed for Glut4 translocation while leptin KO and P2X7r KO mice showed marked decrease in Glut4 levels primarily in stellate cells. Mechanistically stellate cells showed increase in phosphorylated AKT, Glut4 protein and localization in the membrane following administration of P2X7r agonist or leptin+P2X7r agonist, while use of P2X7r antagonist or AKT inhibitor attenuated the response suggesting that leptin-P2X7r axis in concert but not leptin alone is responsible for the Glut4 induction and translocation. Finally P2X7r-agonist and leptin caused an increase in intracellular glucose and consumption by increasing the activity of hexokinase. In conclusion, the study shows a novel role of leptin-induced P2X7r in modulating Glut4 induction and translocation in hepatic stellate cells, that are key to NASH progression.

Duke Scholars

Published In

Biochim Biophys Acta

DOI

ISSN

0006-3002

Publication Date

January 2016

Volume

1862

Issue

1

Start / End Page

32 / 45

Location

Netherlands

Related Subject Headings

  • Receptors, Purinergic P2X7
  • Rats
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Male
  • Liver
  • Leptin
  • Hepatic Stellate Cells
  • Glucose Transporter Type 4
  • Cytochrome P-450 CYP2E1
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chandrashekaran, V., Das, S., Seth, R. K., Dattaroy, D., Alhasson, F., Michelotti, G., … Chatterjee, S. (2016). Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta, 1862(1), 32–45. https://doi.org/10.1016/j.bbadis.2015.10.009
Chandrashekaran, Varun, Suvarthi Das, Ratanesh Kumar Seth, Diptadip Dattaroy, Firas Alhasson, Gregory Michelotti, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, and Saurabh Chatterjee. “Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis.Biochim Biophys Acta 1862, no. 1 (January 2016): 32–45. https://doi.org/10.1016/j.bbadis.2015.10.009.
Chandrashekaran V, Das S, Seth RK, Dattaroy D, Alhasson F, Michelotti G, et al. Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta. 2016 Jan;1862(1):32–45.
Chandrashekaran, Varun, et al. “Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis.Biochim Biophys Acta, vol. 1862, no. 1, Jan. 2016, pp. 32–45. Pubmed, doi:10.1016/j.bbadis.2015.10.009.
Chandrashekaran V, Das S, Seth RK, Dattaroy D, Alhasson F, Michelotti G, Nagarkatti M, Nagarkatti P, Diehl AM, Chatterjee S. Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta. 2016 Jan;1862(1):32–45.

Published In

Biochim Biophys Acta

DOI

ISSN

0006-3002

Publication Date

January 2016

Volume

1862

Issue

1

Start / End Page

32 / 45

Location

Netherlands

Related Subject Headings

  • Receptors, Purinergic P2X7
  • Rats
  • Non-alcoholic Fatty Liver Disease
  • Mice, Inbred C57BL
  • Male
  • Liver
  • Leptin
  • Hepatic Stellate Cells
  • Glucose Transporter Type 4
  • Cytochrome P-450 CYP2E1