Sherrie
27-01-2007, 08:11 AM
“New” hepatic fat activates PPAR to maintain glucose, lipid, and cholesterol homeostasis
Manu V. Chakravarthy,1,3 Zhijun Pan,1,3 Yimin Zhu,1 Karen Tordjman,1 Jochen G. Schneider,1 Trey Coleman,1
John Turk,1 and Clay F. Semenkovich1,2,*
1Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660
South Euclid Avenue, St. Louis, Missouri 63110
2Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
3These authors contributed equally to this work.
*Correspondence: csemenko@im.wustl.edu
Summary
De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPAR-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPAR target genes in FASKOL mice were corrected with a PPAR agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPAR agonist.
These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous
activators of distinct physiological pools of PPAR in adult liver.
Available in full (free) (http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413105001105)
Manu V. Chakravarthy,1,3 Zhijun Pan,1,3 Yimin Zhu,1 Karen Tordjman,1 Jochen G. Schneider,1 Trey Coleman,1
John Turk,1 and Clay F. Semenkovich1,2,*
1Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660
South Euclid Avenue, St. Louis, Missouri 63110
2Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
3These authors contributed equally to this work.
*Correspondence: csemenko@im.wustl.edu
Summary
De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPAR-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPAR target genes in FASKOL mice were corrected with a PPAR agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPAR agonist.
These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous
activators of distinct physiological pools of PPAR in adult liver.
Available in full (free) (http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413105001105)