This review summarizes recent research implicating Forkhead box (Fox)O1, a key transcription factor in glucose metabolism, in the regulation of hepatic lipid metabolism. Insulin dysregulation leading to hypertriglyceridemia is associated with increased hepatic VLDL secretion. FoxO1 is integrated in action with other regulatory factors in VLDL metabolism. The role of FoxO1 is defined in context of recent controversies.
FoxO1 regulates transcription of microsomal triglyceride transfer protein and apolipoprotein (apo)CIII involved in hepatic assembly and postsecretory catabolism of VLDL. Insulin activation of Akt leads to the phosphorylation of FoxO1 with nuclear exclusion and loss of transcriptional activity. Reduced insulin action increases FoxO1 activity and induces microsomal triglyceride transfer protein favoring VLDL assembly and induces apoCIII reducing peripheral triglyceride catabolism. This new mechanistic link between insulin resistance and VLDL overproduction and hypertriglyceridemia compounds effects of other known VLDL regulatory factors.
This review highlights recent advances in research of insulin regulation of hepatic VLDL metabolism. Formation of VLDL requires lipid, apoB structural protein, and microsomal triglyceride transfer protein. FoxO1 is a major factor in hepatic microsomal triglyceride transfer protein regulation. A unifying hypothesis is presented linking regulation of the three necessary hepatic components for VLDL assembly with insulin action and insulin resistance.
aDepartment of Pathology and Laboratory Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA
bRangos Research Center, Children's Hospital of Pittsburgh, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Correspondence to Janet D. Sparks, PhD, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Avenue, Rochester, NY 14642, USA Tel: +1 585 275 7755; fax: +1 585 756 5337; e-mail: Janet_Sparks@urmc.rochester.edu