Adrenal Cell Aldosterone Production Is Stimulated by Very-Low-Density Lipoprotein (VLDL)

Abstract

Very low-density lipoproteins (VLDL) are a class of large lipoprotein synthesized in the liver. The key function of VLDL, in vivo, is to carry triglyceride from the liver to adipose tissue. As a steroidogenic organ, the adrenal gland mainly uses lipoproteins as sources of cholesterol. Although VLDL receptors have been detected in the human adrenal, the function of VLDL in the adrenal gland remains unknown. Herein, we used primary cultures of human and bovine adrenal cells and the adrenocortical cell line H295R as models to determine the effects of VLDL on adrenal steroidogenesis. Our studies revealed that VLDL significantly increased aldosterone synthesis in all of the models tested. This increase was largely due to VLDL's stimulation of the expression of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2). VLDL increased CYP11B2 mRNA expression in a concentration-dependent manner. Effects of VLDL on CYP11B2 transcript levels were not additive with angiotensin II or potassium but were additive with the cAMP pathway agonists ACTH and forskolin. Nifedipine completely inhibited the effects of VLDL on CYP11B2 mRNA, suggesting that calcium is the main signal transduction pathway used by VLDL in adrenal cells. Indeed, VLDL increased cytosolic free calcium levels. An in vivo study conducted in sucrose-fed rats showed a positive correlation between elevated triglyceride (VLDL) levels in plasma and CYP11B2 expression in the adrenal. In conclusion, we have shown that VLDL can stimulate aldosterone synthesis in adrenocortical cells by increasing StAR and CYP11B2 expression, an event likely mediated by a calcium-initiated signaling cascade.

Obesity, hypertension and aldosterone: is leptin the link?

“…Phospholipase D has also been found to mediate aldosterone production and CYP11B2 expression in response to VLDL (Tsai et al 2014), similarly to its role in AngII-induced steroidogenesis. Finally, we also showed that rats on a chow and liquid-sucrose diet that induces obesity and insulin resistance exhibit increased aldosterone synthase levels correlating with elevated triglyceride levels (a measure of VLDL levels in fasted animals) in vivo (Xing et al 2012).…”

“…In the H295R cell line, the effects of VLDL on CYP11B2 transcript levels are not additive with high AngII or elevated extracellular potassium levels, but are additive with the cAMP-elevating agents ACTH and forskolin (Xing et al 2012) and are not altered by exposure to an AT1R antagonist (Tsai et al 2014). The effect of VLDL on aldosterone and CYP11B2 involves the calcium signaling pathway, as the changes can be inhibited by antagonists 230:1 of voltage-dependent L-type calcium channels and calcium/calmodulin-dependent protein kinases (Xing et al 2012). Phospholipase D has also been found to mediate aldosterone production and CYP11B2 expression in response to VLDL (Tsai et al 2014), similarly to its role in AngII-induced steroidogenesis.…”

“…Using pharmacologic inhibitors, these authors also demonstrated that the effects of modified and unmodified VLDL are mediated by cAMP-dependent protein kinase, ERK1/2 and Janus kinase-2 through scavenger receptor class B, member 1 (Saha et al 2012a). High-density lipoprotein also increases aldosterone production (Xing et al 2011, Saha et al 2012b, although its effects are less robust and more variable (Xing et al 2012, Saha et al 2012b. On the other hand, while some investigators have detected a steroidogenic effect of LDL (Saha et al 2012b), the ability of this lipoprotein to stimulate aldosterone production remains controversial (Capponi 2002).…”

“…In recent studies, we showed in primary cultures of human adrenocortical and bovine glomerulosa cells, as well as the adrenocortical cell line, H295R, and its clone the HAC15 cell line, that VLDL significantly increases aldosterone synthesis in these various models of zona glomerulosa cells (Xing et al 2012, Tsai et al 2014). This stimulation occurs at physiological VLDL levels of 30-100 µg protein/mL and is largely due to VLDL's stimulation of the expression of steroidogenic acute regulatory protein and CYP11B2 (Xing et al 2012).…”

“…This stimulation occurs at physiological VLDL levels of 30-100 µg protein/mL and is largely due to VLDL's stimulation of the expression of steroidogenic acute regulatory protein and CYP11B2 (Xing et al 2012). In the H295R cell line, the effects of VLDL on CYP11B2 transcript levels are not additive with high AngII or elevated extracellular potassium levels, but are additive with the cAMP-elevating agents ACTH and forskolin (Xing et al 2012) and are not altered by exposure to an AT1R antagonist (Tsai et al 2014). The effect of VLDL on aldosterone and CYP11B2 involves the calcium signaling pathway, as the changes can be inhibited by antagonists 230:1 of voltage-dependent L-type calcium channels and calcium/calmodulin-dependent protein kinases (Xing et al 2012).…”