Diabetic
dyslipidemia is characterized by increased circulatory
very-low-density lipoprotein (VLDL) levels.
Aldosterone, apart from its role in fluid and
electrolyte homeostasis, has also been implicated in
insulin resistance and myocardial
fibrosis. The impact of VLDL as a potential risk factor for
aldosterone-mediated cardiovascular injury in
diabetes mellitus, however, remains to be investigated. We have therefore studied native and modified VLDL-mediated steroidogenesis and its underlying molecular mechanisms in human
adrenocortical carcinoma cells, NCI H295R. Native VLDL (natVLDL), isolated from healthy volunteers, was subjected to in vitro modification with
glucose (200 mmol/l) or
sodium hypochlorite (1.5 mmol/l) for preparation of glycoxidized and oxidized VLDL, respectively. VLDL treatment induced steroidogenesis in both a concentration- and time-dependent manner. Native and glycoxidized VLDL (50 μg/ml) were almost two-fold more potent in adrenocortical
aldosterone release than
angiotensin II (100 nmol/l). These forms of VLDL significantly augmented transcriptional regulation of
aldosterone synthase (
Cyp11B2), partially through
scavenger receptor class B type I, as evident from the effect of BLT-1. In contrast to glycoxidized VLDL, oxidized VLDL significantly attenuated the stimulatory effect of natVLDL on adrenocortical
hormone synthesis. Moreover, treatment with specific pharmacological inhibitors (
H89,
U0126,
AG490) provided supporting evidence that VLDL, irrespective of modification, presumably recruited PKA, ERK1/2 and Jak-2 for
steroid hormone release through modulation of
Cyp11B2 mRNA level. In conclusion, this study demonstrates a novel insight into intracellular mechanism of VLDL-mediated
aldosterone synthesis through transcriptional regulation of
steroidogenic acute regulatory protein (StAR) and
Cyp11B2 expression in human
adrenocortical carcinoma cell line.