Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis.
Alcohol-induced hepatic steatosis is a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signalling has been shown to significantly regulate lipid metabolism; however, the role of altered cAMP homeostasis in alcohol-mediated hepatic steatosis has never been studied. Our previous work demonstrated that increased expression of hepatic phosphodiesterase 4 (Pde4), which specifically hydrolyses and decreases cAMP levels, plays a pathogenic role in the development of liver inflammation/injury. The aim of this study was to examine the role of PDE4 in alcohol-induced hepatic steatosis. C57BL/6 wild-type and Pde4b knockout (Pde4b(-/-) ) mice were pair-fed control or ethanol liquid diets. One group of wild-type mice received rolipram, a PDE4-specific inhibitor, during alcohol feeding. We demonstrate for the first time that an early increase in PDE4 enzyme expression and a resultant decrease in hepatic cAMP levels are associated with the significant reduction in carnitine palmitoyltransferase 1A (Cpt1a) expression. Notably, alcohol-fed (AF) Pde4b(-/-) mice and AF wild-type mice treated with rolipram had significantly lower hepatic free fatty acid content compared with AF wild-type mice. Importantly, PDE4 inhibition in alcohol-fed mice prevented the decrease in hepatic Cpt1a expression via the Pparα/Sirt1/Pgc1α pathway. These results demonstrate that the alcohol- induced increase in hepatic Pde4, specifically Pde4b expression, and compromised cAMP signalling predispose the liver to impaired fatty acid oxidation and the development of steatosis. Moreover, these data also suggest that hepatic PDE4 may be a clinically relevant therapeutic target for the treatment of alcohol-induced hepatic steatosis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.
Diana V
DV
Avila
Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA.
David F
DF
Barker
Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA.
JingWen
J
Zhang
Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.|Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA.|Robley Rex VA Medical Center, Louisville, Kentucky, USA.
Craig J
CJ
McClain
Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.|Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA.
Shirish
S
Barve
Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, Kentucky, USA.|Department of Internal Medicine, University of Louisville Medical Center, Louisville, Kentucky, USA.
Leila
L
Gobejishvili
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000431:Ethanol; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology
D005230:Fatty Acids, Nonesterified; D058988:Phosphodiesterase 4 Inhibitors; D000431:Ethanol; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C543000:PDE4B protein, mouse; D020889:Rolipram
PDE4; PGC1α, SIRT1, CPT1A; PPARα; alcohol; cAMP; hepatic steatosis