Metabolic syndrome without obesity: hepatic overexpression of 11β-hydroxysteroid dehydrogenase type 1 in transgenic mice

JM Paterson, NM Morton, C Fievet… - Proceedings of the …, 2004 - National Acad Sciences
JM Paterson, NM Morton, C Fievet, CJ Kenyon, MC Holmes, B Staels, JR Seckl, JJ Mullins
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
In obese humans and rodents there is increased expression of the key glucocorticoid (GC)
regenerating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in adipose
tissue. This increased expression appears to be of pathogenic importance because
transgenic mice overexpressing 11β-HSD1 selectively in adipose tissue exhibit a full
metabolic syndrome with visceral obesity, dyslipidemia, insulin-resistant diabetes, and
hypertension. In this model, while systemic plasma GC levels are unaltered, GC delivery to …
In obese humans and rodents there is increased expression of the key glucocorticoid (GC) regenerating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in adipose tissue. This increased expression appears to be of pathogenic importance because transgenic mice overexpressing 11β-HSD1 selectively in adipose tissue exhibit a full metabolic syndrome with visceral obesity, dyslipidemia, insulin-resistant diabetes, and hypertension. In this model, while systemic plasma GC levels are unaltered, GC delivery to the liver via the portal vein is increased. 11β-HSD1 is most highly expressed in liver where inhibition or deficiency of its activity improves glucose and lipid homeostasis. To determine the potential contribution of elevated intrahepatic GCs alone toward development of insulin-resistant syndromes we generated transgenic mice expressing increased 11β-HSD1 activity selectively in the liver under transcriptional control of hepatic regulatory sequences derived from the human apoE gene (apoE-HSD1). Transgenic lines with 2- and 5-fold-elevated 11β-HSD1 activity exhibited mild insulin resistance without altered fat depot mass. ApoE-HSD1 transgenic mice exhibited fatty liver and dyslipidemia with increased hepatic lipid synthesis/flux associated with elevated hepatic LXRα and PPARα mRNA levels as well as impaired hepatic lipid clearance. Further, apoE-HSD1 transgenic mice have a marked, transgene-dose-associated hypertension paralleled by incrementally increased liver angiotensinogen expression. These data suggest that elevated hepatic expression of 11β-HSD1 may relate to the pathogenesis of specific fatty liver, insulin-resistant, and hypertensive syndromes without obesity in humans as may occur in, for example, myotonic dystrophy, and possibly, the metabolically obese, normal-weight individual.
National Acad Sciences