Dehydroepiandrosterone activates cyclic adenosine 3′,5′-monophosphate/protein kinase A signalling and suppresses sterol regulatory element-binding protein-1 expression in cultured primary chicken hepatocytes

Abstract

Dehydroepiandrosterone (DHEA), a steroid hormone that is secreted by the adrenal cortex in mammals, has an array of biological actions, including inhibition of fat synthesis, decreasing the number of adipocytes, and a reduction in mammalian metabolic efficiency. Recent studies showed that DHEA may decrease fat deposition in poultry, but the mechanism of action is unclear. In the present study, we demonstrate that DHEA stimulates intracellular cyclic adenosine 3 0 ,5 0 -monophosphate (cAMP) accumulation in chicken hepatocytes during a 30 min incubation period. Increases in intracellular cAMP are evoked by as low as 0·1 mM-DHEA. The cAMP induced by DHEA, while suppressing cAMP-specific phosphodiesterase activity, also activates cAMP-dependent protein kinase A (PKA) in chicken hepatocytes. In addition, the activation of PKA leads to down-regulation of sterol regulatory element-binding protein-1 (SREBP-1). These findings demonstrate that direct action by DHEA leads to activation of the cAMP/PKA signalling system in the modulation of lipid metabolism by repressing SREBP-1, thereby providing a novel explanation for some of the underlying effects proposed for DHEA in the prevention of fat deposition in poultry.Dehydroepiandrosterone: Hepatic lipid metabolism: Lipogenesis: Cultured primary chicken hepatocytes Cyclic adenosine 3 0 ,5 0 -monophosphate (cAMP) is an integral constituent of the kinase cascade that links a number of extracellular signals to a variety of cellular functions. Under physiological conditions, the biosynthesis of lipids in the liver is negatively regulated, at least in part, by the elevated intracellular level of cAMP (1 -3) . Glucagon, the adrenalines, and other reagents raise the cellular cAMP concentration level and reduce the activity or level of hepatic lipogenic enzymes (4,5) such as fatty acid synthase, stearoyl-CoA desaturase, and glycerol-3-phosphate acyltransferase. The cAMPdependent kinase, protein kinase A (PKA), which is a major protein kinase activated by cAMP, has been shown to be involved in lipid metabolism as well (6,7) . Hepatic fatty acid synthesis and fatty acid synthesis in cultured hepatocytes, mediated by sterol regulatory element-binding protein (SREBP)-1, a transcription factor that regulates genes controlling intracellular lipid metabolism, have been shown to be negatively affected by cAMP (8) . It has also been demonstrated that cAMP inhibits insulin-regulated SREBP-1 mRNA levels and the expression of the SREBP-1-regulated genes involved in lipogenesis (9) . However, the molecular mechanism underlying this inhibitory function is still unclear.Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in circulation (10)

SREBP: a novel therapeutic target

“…The cAMP-dependent kinase, protein kinase A (PKA), has been shown to be involved in lipid metabolism. Under physiological conditions, hepatic lipogenic enzymes, such as FASN, stearoyl-CoA desaturase (SCD), and glycerol-3-phosphate acyltransferase (GPAT), are negatively regulated by the elevated intracellular level of cAMP [61].…”

Dehydroepiandrosterone Reduced Lipid Droplet Accumulation via Inhibiting Cell Proliferation and Improving Mitochondrial Function in Primary Chicken Hepatocytes

“…Our previous study found that DHEA treatment reduced fat deposition in broiler chicken or chicken embryos (Tang et al 2007, Zhao et al 2007, Huang et al 2010. In addition, we found that DHEA accelerates lipid catabolism by direct regulation of hepatic gene expression, and this action mainly achieved by activation of cAMP/PKA signaling pathway in primary chicken hepatocytes (Tang et al 2009a, Tang et al 2009b. Importantly, most of the mitochondria in DHEA-treated hepatocytes presented a high electron density based on morphological observations, indicating that DHEA might influence mitochondrial function in primary chicken hepatocytes (Tang et al 2009a).…”

“…Unlike mammalian species, the liver is the most important organ of fat metabolism in poultry (Griffin et al 1992). Our previous study found that DHEA treatment reduced fat deposition in broiler chicken or chicken embryos (Tang et al 2007, Zhao et al 2007, Huang et al 2010. In addition, we found that DHEA accelerates lipid catabolism by direct regulation of hepatic gene expression, and this action mainly achieved by activation of cAMP/PKA signaling pathway in primary chicken hepatocytes (Tang et al 2009a, Tang et al 2009b.…”

“…In addition, we found that DHEA accelerates lipid catabolism by direct regulation of hepatic gene expression, and this action mainly achieved by activation of cAMP/PKA signaling pathway in primary chicken hepatocytes (Tang et al 2009a, Tang et al 2009b. Importantly, most of the mitochondria in DHEA-treated hepatocytes presented a high electron density based on morphological observations, indicating that DHEA might influence mitochondrial function in primary chicken hepatocytes (Tang et al 2009a). As well known, the expansion of fat mass is due to increased adipocyte hypertrophy and hyperplasia in broiler chickens (Butterwith 1997).…”

“…DHEA had been termed "the wonder hormone" due to it protects against mood depressed (Souza-Teodoro et al 2016), obesity (Hansen et al 1997, Sato et al 2012), cancer (Arnold et al 2008), cardiovascular (Boxer et al 2010) and aginginduced changes to the brain (Kurita et al 2013, Soma et al 2015. Previous study certified that DHEA promoted a variety of illnesses associated with aging, and it is widely available as a dietary supplemental over all the United States (Vacheron-Trystram et al 2002).…”