PMID- 29247122
OWN - NLM
STAT- MEDLINE
DCOM- 20190107
LR  - 20220330
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 32
IP  - 5
DP  - 2018 May
TI  - Prostaglandin I(2) suppresses the development of diet-induced nonalcoholic 
      steatohepatitis in mice.
PG  - 2354-2365
LID - 10.1096/fj.201700590R [doi]
AB  - Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic 
      syndrome. Although the prostaglandin (PG)I(2) receptor IP is expressed broadly in 
      the liver, the role of PGI(2)-IP signaling in the development of NASH remains to 
      be determined. Here, we investigated the role of the PGI(2)-IP system in the 
      development of steatohepatitis using mice lacking the PGI(2) receptor IP 
      [IP-knockout (IP-KO) mice] and beraprost (BPS), a specific IP agonist. IP-KO and 
      wild-type (WT) mice were fed a methionine- and choline-deficient diet (MCDD) for 
      2, 5, or 10 wk. BPS was administered orally to mice every day during the 
      experimental periods. The effect of BPS on the expression of chemokine and 
      inflammatory cytokines was examined also in cultured Kupffer cells. WT mice fed 
      MCDD developed steatohepatitis at 10 wk. IP-KO mice developed steatohepatitis at 
      5 wk with augmented histologic derangements accompanied by increased hepatic 
      monocyte chemoattractant protein-1 (MCP-1) and TNF-alpha concentrations. After 10 wk 
      of MCDD, IP-KO mice had greater hepatic iron deposition with prominent oxidative 
      stress, resulting in hepatocyte damage. In WT mice, BPS improved histologic and 
      biochemical parameters of steatohepatitis, accompanied by reduced hepatic 
      concentration of MCP-1 and TNF-alpha. Accordingly, BPS suppressed the LPS-stimulated 
      Mcp-1 and Tnf-alpha mRNA expression in cultured Kupffer cells prepared from WT mice. 
      PGI(2)-IP signaling plays a crucial role in the development and progression of 
      steatohepatitis by modulating the inflammatory response, leading to augmented 
      oxidative stress. We suggest that the PGI(2)-IP system is an attractive 
      therapeutic target for treating patients with NASH.-Kumei, S., Yuhki, K.-I., 
      Kojima, F., Kashiwagi, H., Imamichi, Y., Okumura, T., Narumiya, S., Ushikubi, F. 
      Prostaglandin I(2) suppresses the development of diet-induced nonalcoholic 
      steatohepatitis in mice.
FAU - Kumei, Shima
AU  - Kumei S
AD  - Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
AD  - Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan.
FAU - Yuhki, Koh-Ichi
AU  - Yuhki KI
AD  - Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
FAU - Kojima, Fumiaki
AU  - Kojima F
AD  - Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
FAU - Kashiwagi, Hitoshi
AU  - Kashiwagi H
AD  - Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
FAU - Imamichi, Yoshitaka
AU  - Imamichi Y
AD  - Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
FAU - Okumura, Toshikatsu
AU  - Okumura T
AD  - Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan.
FAU - Narumiya, Shuh
AU  - Narumiya S
AD  - Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan.
FAU - Ushikubi, Fumitaka
AU  - Ushikubi F
AD  - Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171215
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Receptors, Epoprostenol)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 35E3NJJ4O6 (beraprost)
RN  - DCR9Z582X0 (Epoprostenol)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Epoprostenol/analogs & derivatives/*pharmacology
MH  - Food, Formulated/*adverse effects
MH  - Gene Expression Regulation/drug effects
MH  - Hepatocytes/*metabolism/pathology
MH  - Kupffer Cells/*metabolism/pathology
MH  - Liver/*metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Non-alcoholic Fatty Liver Disease/genetics/metabolism/pathology/*prevention & 
      control
MH  - Oxidative Stress/drug effects/genetics
MH  - Receptors, Epoprostenol/agonists/genetics/metabolism
MH  - Time Factors
MH  - Tumor Necrosis Factor-alpha/biosynthesis/genetics
OTO - NOTNLM
OT  - Kupffer cell
OT  - NASH
OT  - oxidative stress
EDAT- 2017/12/17 06:00
MHDA- 2019/01/08 06:00
CRDT- 2017/12/17 06:00
PHST- 2017/12/17 06:00 [pubmed]
PHST- 2019/01/08 06:00 [medline]
PHST- 2017/12/17 06:00 [entrez]
AID - fj.201700590R [pii]
AID - 10.1096/fj.201700590R [doi]
PST - ppublish
SO  - FASEB J. 2018 May;32(5):2354-2365. doi: 10.1096/fj.201700590R. Epub 2017 Dec 15.