Vesicular ATP release from hepatocytes plays a role in the progression of nonalcoholic steatohepatitis

Keita Tatsushima, Nao Hasuzawa, Lixiang Wang, Miki Hiasa, Shohei Sakamoto, Kenji Ashida, Nobuyuki Sudo, Yoshinori Moriyama, Masatoshi Nomura

Research output: Contribution to journalArticlepeer-review

Abstract

Non-alcoholic steatohepatitis (NASH) is becoming a growing public health problem along with the increase of metabolic syndrome worldwide. Extracellular nucleotides are known to serve as a danger signal by initiating purinergic signaling in many inflammatory disorders, although the role of purinergic signaling in the progression of NASH remains to be clarified. Vesicular nucleotide transporter (VNUT) is a key molecule responsible for vesicular ATP release to initiate purinergic signaling. Here, we studied the role of VNUT in the progression of nonalcoholic steatohepatitis. VNUT was expressed in mouse hepatocytes and associated, at least in part, with apolipoprotein B (apoB)-containing vesicles. High glucose stimulation evoked release of appreciable amount of ATP from hepatocytes, which disappeared in hepatocytes of Vnut knockout (Vnut−/−) mice. Glucose treatment also stimulated triglyceride secretion from hepatocytes, which was inhibited by PPADS and MRS211, antagonists of P2Y receptors, and clodronate, a VNUT inhibitor, and was significantly reduced in Vnut−/− mice. In vivo, postprandial secretion of triglyceride from hepatocytes was observed, while the serum triglyceride level was significantly reduced in Vnut−/− mice. On a high-fat diet, the liver of wild type mice exhibited severe inflammation, fibrosis, and macrophage infiltration, which is similar to NASH in humans, while this NASH pathology was not observed in Vnut−/− mice. These results suggest that VNUT-mediated vesicular ATP release regulates triglyceride secretion and involves in chronic inflammation in hepatocytes. Since blockade of vesicular ATP release protects against progression of steatohepatitis, VNUT may be a pharmacological target for NASH.

Original languageEnglish
Article number166013
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1867
Issue number3
DOIs
Publication statusPublished - Mar 1 2021

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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