Role of phosphodiesterase-4 in alcohol-induced organ injury.

Alcoholic liver diseases;Neuro-inflammation, Alcohol--Physiological effect;Phosphodiesterases

Diana Veronica Avila

University:University of Louisville

Department:Pharmacology and Toxicology

关键词: Alcoholic liver diseases;    Neuro-inflammation, Alcohol--Physiological effect;    Phosphodiesterases;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=3486&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. Alcohol metabolism leads to generation of free radicals and oxidative stress with a resultant formation of lipid peroxidation products, which, in turn, contribute to the development of ALD. Alcohol induced hepatic steatosis is the earliest and most frequent manifestation of ALD and a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signaling has been shown to significantly regulate lipid metabolism. Moreover, agents that increase cAMP have been shown to effectively mitigate oxidative stress both in vivo and in vitro. Hence, the role of hepatic PDE4 and a resultant dysregulation of cAMP signaling in alcohol induced hepatic steatosis and lipid peroxidation was examined. C57BL/6 wild type (WT) and Pde4b knockout (Pde4b-/-) mice were pair-fed control and ethanol liquid diets. One group of wild type mice received Rolipram, a PDE4 specific inhibitor, during alcohol feeding. Alcohol feeding resulted in a significant fat accumulation and oxidative stress in WT mice as demonstrated by increased hepatic free fatty acid levels and lipid peroxidation. This alcohol effect was associated with a significant decrease in hepatic carnitine palmitoyltransferase 1A (CPT1A) expression, a rate limiting enzyme in fatty acid β-oxidation. Additionally, hepatic F4/80 staining was markedly increased in alcohol fed WT mice, indicating Kupffer cell activation. Importantly, alcohol feeding significantly increased hepatic PDE4 enzyme expression as early as in one week with the concomitant decrease in cAMP/pCREB levels. PDE4 inhibition in alcohol fed mice prevented the decrease in hepatic CPT1A expression and lipid accumulation. This effect on CPT1A expression was mediated by preventing the decrease in a critical transcription factor for CPT1A expression, peroxisome proliferator-activated receptor (PPARα) and increase in PPARα co-activators, peroxisome proliferator-activated receptor gamma coactivator 1α and sirtuin 1(PGC-1α and SIRT1). Moreover, compared to wild type mice, Pde4b knockout and Rolipram treated alcohol fed mice had higher levels of antioxidant enzymes SOD1/2, and GPx1/2 and decreased 4HNE and F4/80 staining. In summary, these results demonstrate that the alcohol- induced increase in hepatic PDE4, specifically PDE4B expression, and compromised cAMP signaling predisposes the liver to impaired fatty acid oxidation and increased oxidative stress. These data also suggest that hepatic PDE4 is a clinically relevant therapeutic target for the treatment of alcoholic fatty liver disease. Chronic ethanol consumption significantly increases brain TLR4 expression and downstream inflammatory gene expression, contributing to microglial