title: The liver-selective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet.
abstract: OBJECTIVE
  There is an unmet medical need for novel NAFLD treatments. Here we have examined the effects of liver-selective NO donor (V-PYRRO/NO) as compared with metformin on hepatic steatosis and glucose tolerance in mice fed high fat diet.
  
  
  METHODS
  Effects of V-PYRRO/NO (5 mgkg(-1)) or metformin (616 mgkg(-1)) were examined in C57BL/6J mice fed high fat diet (HF, 60 kcal% fat). Quantitative determination of steatosis, liver fatty acid composition and western blot analysis of selected proteins involved in mitochondrial biogenesis, fatty acid de novo synthesis and oxidation, triacylglycerols and cholesterol transport from the liver were performed. Liver NOx and nitrate concentration and blood biochemistry were also analyzed.
  
  
  RESULTS
  V-PYRRO/NO and metformin reduced liver steatosis with simultaneous reduction of total liver triacylglycerols, diacylglycerols and ceramides fraction and reversed HF-induced decrease in UFA/SFA ratio. V-PYRRO/NO substantially improved postprandial glucose tolerance, while the effect of metformin was modest and more pronounced on HOMA IR index. The anti-steatotic mechanism of V-PYRRO/NO was dependent on NO release, differed from that of metformin and involved improved glucose tolerance and inhibition of de novo fatty acid synthesis by Akt activation and ACC phosphorylation. In turn, major mechanism of metformin action involved increased expression of proteins implicated in mitochondrial biogenesis and metabolism (PGC-1α, PPARα, COX IV, cytochrome c, HADHSC).
  
  
  CONCLUSIONS
  V-PYRRO/NO acts as a liver-specific NO donor prodrug affording pronounced anti-steatotic effects and may represent an efficient, mechanistically novel approach to prevent liver steatosis and insulin resistance.
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: edyta.maslak@jcet.eu.
authors.forename: Edyta
authors.initials: E
authors.lastname: Maslak
authors.affiliation: Department of Physiology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. Electronic address: piotrz@umb.edu.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Zabielski
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. Electronic address: kochan@chemia.uj.edu.pl.
authors.forename: Kamila
authors.initials: K
authors.lastname: Kochan
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: kamil.kus@jcet.eu.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kus
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: agnieszka.jasztal@jcet.eu.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jasztal
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: barbara.sitek@jcet.eu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: bartosz.proniewski@jcet.eu.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Proniewski
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: tomasz.wojcik@jcet.eu.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wojcik
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: katarzyna.gula@jcet.eu.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gula
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: agnieszka.kij@jcet.eu.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kij
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. Electronic address: maria.walczak@jcet.eu.
authors.forename: Maria
authors.initials: M
authors.lastname: Walczak
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. Electronic address: baranska@chemia.uj.edu.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Baranska
authors.affiliation: Department of Physiology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. Electronic address: adrian@umb.edu.pl.
authors.forename: Adrian
authors.initials: A
authors.lastname: Chabowski
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States. Electronic address: hollandrj@mail.nih.gov.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Holland
authors.affiliation: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States. Electronic address: saavedjo@mail.nih.gov.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States. Electronic address: keeferl@mail.nih.gov.
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Department of Experimental Pharmacology (Chair of Pharmacology), Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D005951:Glucose Tolerance Test / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D019518:Postprandial Period / Q000187:drug effects* / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D020011:Protective Agents; D011759:Pyrrolidines
keywords: Fatty acid metabolism; Glucose tolerance; Hepatoprotection; Liver steatosis; Nitric oxide