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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Tatsushima, Keita^1,2,3  Hasuzawa, Nao^1,4  Wang, Lixiang⁵  Hiasa, Miki⁶  Sakamoto, Shohei¹  Ashida, Kenji^1,4  Sudo, Nobuyuki²  Moriyama, Yoshinori^4,6  Nomura, Masatoshi^1,4 

[1] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 8128582, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Psychosomat Med, Fukuoka 8128582, Japan

[3] Toranomon Gen Hosp, Endocrine Ctr, Tokyo 1058470, Japan

[4] Kurume Univ, Dept Internal Med, Div Endocrinol & Metab, Sch Med, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan

[5] Kurume Univ, Dept Med Biochem, Sch Med, Kurume, Fukuoka 8300011, Japan

[6] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Membrane Biochem, Okayama 7008530, Japan

关键词: ATP;    Inflammation;    NASH;    Triglyceride;    VNUT;    Hepatocyte;    VLDL;    Apolipoprotein B;    SLC17A9;    Purinergic signaling;   

DOI  :  10.1016/j.bbadis.2020.166013

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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