Chronic ethanol consumption disrupts G protein-dependent signaling pathways in rat adipocytes.
Chronic ethanol consumption disrupts G protein-dependent signaling pathways in rat adipocytes. cAMP focus in adipocytes FXV 673 did not differ between pair- and ethanol-fed rats. The suppression in cAMP accumulation caused by ethanol feeding was associated with increased activity of phosphodiesterase 4. Chronic ethanol feeding also decreased β-adrenergic receptor-stimulated protein kinase A activation and phosphorylation of its downstream proteins perilipin A and hormone-sensitive lipase the primary lipase-mediating lipolysis. In conclusion these data suggest that chronic ethanol feeding increased phosphodiesterase 4 activity in adipocytes resulting in decreased accumulation of cAMP in response to β-adrenergic activation and a suppression of β-adrenergic stimulation of lipolysis. CHRONIC HEAVY ETHANOL consumption which is associated with hepatic pancreatic and myocardial diseases as well as insulin resistance and type 2 diabetes is one of the most common health problems in the United States with high morbidity and mortality (1). Although the exact mechanisms by which chronic ethanol contributes to these pathophysiological conditions are unknown the disruption of lipid homeostasis by ethanol is usually a likely FXV 673 contributor to disease progression. For example chronic ethanol administration causes excess accumulation of fat in liver with the eventual development of hepatic steatosis in both humans and animal models Rabbit Polyclonal to ACAD10. (2). Chronic ethanol feeding to rats induces hyperlipidemia coupled with elevated plasma cholesterol triglyceride and free fatty acid concentrations (3). Adipose tissue the biggest storage pool of lipids plays an important role for maintaining whole-body lipid homeostasis. FXV 673 However the effects of chronic ethanol feeding on lipid metabolism in adipose tissues are unknown. Lipolysis is defined as hydrolysis of triglycerides the major form of stored energy in adipose tissue. Tight regulation of lipolysis is critical because mobilization of free fatty acid and glycerol from adipose tissue supplies other tissues with metabolites and energy substrates FXV 673 during fasting and in response to contamination and inflammation (4). Moreover free fatty acids released during lipolysis acting as ligands for transcription factors regulate expression of genes involved FXV 673 in lipid and energy metabolism during fasting and stress (5). Lipolysis in adipocytes is usually regulated by a number of hormones such as ACTH epinephrine norepinephrine and insulin (6). Catecholamine-induced lipolysis is usually well characterized initiated by stimulation of β-adrenergic receptors which are coupled to activation of adenylyl cyclase by the heterotrimeric Gαs protein which in turn converts ATP to cAMP. cAMP-dependent protein kinase A (PKA) then phosphorylates two main targets hormone-sensitive lipase (HSL) the primary lipase responsible for hydrolysis of triglycerides as well as perilipin A the coating protein of lipid droplets. In unstimulated adipocytes perilipin A functions as a barrier to lipolysis because of its location on the surface of lipid droplets preventing the conversation of HSL with the lipid droplet (7). In response to FXV 673 β-adrenergic activation phosphorylated perilipin A undergoes a conformational change which is essential for proper translocation of HSL from the cytosol to the surface of lipid droplets and subsequent attachment to triglycerides leading to initiation of triglyceride hydrolysis (7 8 Chronic ethanol exposure disrupts receptor-activated signal transduction in a variety of cell types (9). One target of ethanol is the G protein-mediated signaling pathways (9). The effect of ethanol on G protein-dependent responses is usually cell type specific. In adipocytes ethanol feeding for 4 wk causes a sensitization to stimulation by the β-adrenergic agonist isoproterenol as well as an increase in the quantity of immunoreactive Gαs protein (10). Because lipolysis in adipocytes is usually regulated by a G protein-dependent signaling pathway known to be affected by chronic ethanol we hypothesized that β-adrenergic receptor regulation of lipolysis may also be susceptible to long-term ethanol exposure. In the present work we report that 4-wk ethanol feeding to.