PMID- 33790119
OWN - NLM
STAT- MEDLINE
DCOM- 20210702
LR  - 20240226
IS  - 1347-5231 (Electronic)
IS  - 0031-6903 (Linking)
VI  - 141
IP  - 4
DP  - 2021
TI  - [VNUT Is a Therapeutic Target for Type 2 Diabetes and NASH].
PG  - 517-526
LID - 10.1248/yakushi.20-00204-4 [doi]
AB  - ATP, used in cells as an energy currency, also acts as an extracellular signaling 
      molecule. Studies of purinergic receptor subtypes have revealed that purinergic 
      chemical transmission plays important roles in various cell types. The vesicular 
      nucleotide transporter (VNUT), the ninth transporter in the SLC17 organic anion 
      transporter family, is essential for vesicular ATP storage and its subsequent 
      release. The VNUT is localized on the membrane of secretory vesicles and actively 
      transports ATP into vesicles using an electrochemical gradient of protons 
      supplied by vacuolar proton ATPase (V-ATPase) as a driving force. ATP acts as a 
      damage-associated molecular pattern (DAMPs), contributing to the persistence of 
      chronic inflammation. Chronic inflammation induces systemic insulin resistance, 
      which is the underlying pathology of type 2 diabetes and non-alcoholic fatty 
      liver disease (NAFLD), ranging from simple steatosis to non-alcoholic 
      steatohepatitis (NASH). We previously demonstrated that ATP transported in 
      insulin granules via the VNUT negatively regulates insulin secretion. We also 
      found that hepatocytes release ATP in a VNUT-dependent manner, which elicits 
      hepatic insulin resistance and inflammation. VNUT-knockout mice exhibited 
      improved glucose tolerance and were resistant to the development of high fat 
      diet-induced NAFLD. In this article, we summarize recent advances in our 
      understanding of the mechanism of the VNUT, the development of inhibitors, and 
      its pathological involvement in type 2 diabetes and NAFLD. The pharmacological 
      inhibition of the VNUT may represent a potential therapeutic approach for the 
      treatment of metabolic diseases.
FAU - Hasuzawa, Nao
AU  - Hasuzawa N
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume 
      University School of Medicine.
FAU - Tatsushima, Keita
AU  - Tatsushima K
AD  - Department of Endocrinology and Metabolism, Toranomon Hospital.
FAU - Tokubuchi, Rie
AU  - Tokubuchi R
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume 
      University School of Medicine.
FAU - Kabashima, Masaharu
AU  - Kabashima M
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume 
      University School of Medicine.
FAU - Nomura, Masatoshi
AU  - Nomura M
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume 
      University School of Medicine.
LA  - jpn
PT  - Journal Article
PT  - Review
PL  - Japan
TA  - Yakugaku Zasshi
JT  - Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
JID - 0413613
RN  - 0 (Nucleotide Transport Proteins)
RN  - 0 (Slc17a9 protein, human)
RN  - 0813BZ6866 (Clodronic Acid)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Clodronic Acid/pharmacology/therapeutic use
MH  - Diabetes Mellitus, Type 2/*drug therapy/*genetics
MH  - Drug Discovery
MH  - Humans
MH  - Insulin Resistance/genetics
MH  - Insulin Secretion/genetics
MH  - Mice, Knockout
MH  - *Molecular Targeted Therapy
MH  - Non-alcoholic Fatty Liver Disease/*drug therapy/*genetics
MH  - Nucleotide Transport Proteins/antagonists & inhibitors/*physiology
MH  - Secretory Vesicles/metabolism
MH  - Mice
OTO - NOTNLM
OT  - ATP
OT  - diabetes
OT  - non-alcoholic fatty liver disease
OT  - purinergic signaling
OT  - vesicular nucleotide transporter
EDAT- 2021/04/02 06:00
MHDA- 2021/07/03 06:00
CRDT- 2021/04/01 05:53
PHST- 2021/04/01 05:53 [entrez]
PHST- 2021/04/02 06:00 [pubmed]
PHST- 2021/07/03 06:00 [medline]
AID - 10.1248/yakushi.20-00204-4 [doi]
PST - ppublish
SO  - Yakugaku Zasshi. 2021;141(4):517-526. doi: 10.1248/yakushi.20-00204-4.