TY - JOUR
T1 - The liver-selective NO donor, V-PYRRO/NO, protects against liver steatosis and improves postprandial glucose tolerance in mice fed high fat diet
AU - Maslak, Edyta
AU - Zabielski, Piotr
AU - Kochan, Kamila
AU - Kus, Kamil
AU - Jasztal, Agnieszka
AU - Sitek, Barbara
AU - Proniewski, Bartosz
AU - Wojcik, Tomasz
AU - Gula, Katarzyna
AU - Kij, Agnieszka
AU - Walczak, Maria
AU - Baranska, Malgorzata
AU - Chabowski, Adrian
AU - Holland, Ryan J.
AU - Saavedra, Joseph E.
AU - Keefer, Larry K.
AU - Chlopicki, Stefan
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Background and purpose: 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. Material and methods: Effects of V-PYRRO/NO (5 mg kg-1) or metformin (616 mg kg-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.
AB - Background and purpose: 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. Material and methods: Effects of V-PYRRO/NO (5 mg kg-1) or metformin (616 mg kg-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.
KW - Fatty acid metabolism
KW - Glucose tolerance
KW - Hepatoprotection
KW - Liver steatosis
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=84921869378&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2014.12.004
DO - 10.1016/j.bcp.2014.12.004
M3 - Article
C2 - 25534988
AN - SCOPUS:84921869378
SN - 0006-2952
VL - 93
SP - 389
EP - 400
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 3
ER -