Digoxin and ouabain increase the synthesis of cholesterol in human liver cells

• Published in: Cellular and molecular life sciences : CMLS Vol. 66; no. 9; pp. 1580 - 1594
• Main Authors: Campia, I, Gazzano, E, Pescarmona, G, Ghigo, D, Bosia, A, Riganti, C
• Format: Journal Article
• Language: English
• Published: Basel Basel : Birkhäuser-Verlag 01.05.2009; Birkhäuser-Verlag; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cardiotonic Agents - pharmacology; Cardiovascular disease; Cardiovascular diseases; Cell Biology; Cholesterol; Cholesterol - biosynthesis; Digoxin - pharmacology; Enzyme Inhibitors - pharmacology; Enzymes; Hepatocytes - drug effects; Hormones; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Life Sciences; Liver; Lovastatin - analogs & derivatives; Lovastatin - pharmacology; Ouabain - pharmacology; Proteins; Research Article; Steroid hormones; Steroids; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - metabolism; Ubiquinone - metabolism; ouabain; cholesterol; Digoxin; sterol regulatory element binding proteins; 3-hydroxy-3-methylglutaryl-coenzyme A reductase; SREBP-cleavage activating-protein
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-009-9018-5

Digoxin and ouabain are steroid drugs that inhibit the Na⁺/K⁺-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells.