Pomc knockout mice have secondary hyperaldosteronism despite an absence of adrenocorticotropin.

Aldosterone production is controlled by angiotensin II, potassium, and ACTH. Mice lacking Pomc and its pituitary product ACTH have been reported to have absent or low aldosterone levels, suggesting that ACTH is required for normal aldosterone production. However, this is at odds with the clinical finding that human aldosterone deficiency is not a component of secondary adrenal insufficiency. To resolve this, we measured plasma and urine electrolytes, together with plasma aldosterone and renin activity, in Pomc(-/-) mice. We found that these mice have secondary hyperaldosteronism (elevated aldosterone without suppression of renin activity), indicating that ACTH is not required for aldosterone production or release in vivo. Exogenous ACTH stimulates a further increase in aldosterone in Pomc(-/-) mice, whereas angiotensin II has no effect, and the combination of angiotensin II and ACTH is no more potent than ACTH alone. These data suggest that aldosterone production and release in vivo do not require the action of ACTH during development or postnatal life and that secondary hyperaldosteronism in Pomc(-/-) mice is a consequence of glucocorticoid deficiency.

The generation of carcinogenic etheno-DNA adducts in the liver of patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), in particular its more aggressive form nonalcoholic steatohepatitis (NASH) is increasingly observed as a cause of end stage liver disease and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) are an important factor in the pathogenesis of HCC. ROS can react with polyunsaturated fatty acids derived from membrane phospholipids resulting in the production of reactive aldehydes as lipid oxidation (LPO) byproducts, such as 4-hydroxynonenal (4 HNE). 4 HNE can react with DNA to form mutagenic exocyclic etheno-DNA adducts. ROS is induced by inflammatory processes, but also by induction of cytochrome P450 2E1 (CYP2E1), as seen with chronic alcohol consumption. METHODS: Immunohistochemical detection of CYP2E1, 4 HNE and hepatic exocyclic etheno-DNA adducts was performed on liver sections from 39 patients with NFLD. Spearman rank correlation was calculated to examine possible correlations. RESULTS: Exocyclic etheno-DNA adducts were detected and correlated significantly with 4 HNE, but not with CYP2E1. CONCLUSIONS: This is the first description of highly carcinogenic exocyclic etheno-DNA adducts in NAFLD patients. We could show that exocyclic etheno-DNA adducts significantly correlated with lipid peroxidation product 4 HNE, but not with CYP2E1, implying that in NAFLD ROS generation with consecutive DNA damage is rather inflammation driven through various cytokines than by induction of CYP2E1.