FoxO1 integrates insulin signaling to VLDL production

Abstract

Very low-density lipoproteins (VLDL) are triglyceride-rich particles. VLDL is synthesized in hepatocytes and secreted from the liver in a pathway that is tightly regulated by insulin. Hepatic VLDL production is stimulated in response to reduced insulin action, resulting in increased release of VLDL into the blood under fasting conditions. Circulating VLDL serves as a vehicle for transporting lipids to peripheral tissues for energy homeostasis. Conversely, hepatic VLDL production is suppressed in response to increased insulin release after meals. This effect is critical for preventing prolonged excursion of postprandial plasma lipid profiles in normal individuals. In subjects with obesity and type 2 diabetes, the ability of insulin to regulate VLDL production becomes impaired due to insulin resistance in the liver, resulting in excessive VLDL secretion and accumulation of triglyceride-rich particles in the blood. Such abnormality in lipid metabolism characterizes the pathogenesis of hypertriglyceridemia and accounts for increased risk of coronary artery disease in obesity and type 2 diabetes. Nevertheless, the molecular basis that links insulin resistance to VLDL overproduction remains poorly understood. Our recent studies illustrate that the forkhead transcription factor FoxO1 acts in the liver to integrate hepatic insulin action to VLDL production. Augmented FoxO1 activity in insulin resistant livers promotes hepatic VLDL overproduction and predisposes to the development of hypertriglyceridemia. These new findings raise an important question: Is FoxO1 a therapeutic target for ameliorating hypertriglyceridemia? Here we discuss this question in the context of recent advances toward our understanding of the pathophysiology of hypertriglyceridemia.

Components of the metabolic syndrome in early childhood in very-low-birth-weight infants and term small and appropriate for gestational age infants

“…In the present study, we showed that at 1 y of age term born SGA children have a high prevalence of high triglycerides, with the cut-off value based on term born AGA children from the same population. The high prevalence of high triglycerides is probably caused by reduced insulin sensitivity, as insulin resistance in the liver results in very low-density lipoprotein overproduction and development of hypertriglyceridemia (16,17). In this small group, this hypothesis could not be confirmed with the HOMA values.…”

Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes

“…FoxO1 is a transcription factor that plays a key role in the hepatic VLDL assembly and secretion. FoxO1 stimulated the MTTP expression, elevated the ApoB secretion, and augmented the VLDL production though binding and stimulating MTTP promoter activity (Kamagate and Dong, 2008a;Kamagate et al, 2008b). Hepatic steatosis occurs in birds when the increase of lipogenesis exceeds the rate of VLDL assembly and secretion.…”

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

“…In hypertriglyceridemia, more VLDL particles, as measured by apoB, and larger and more TG-and apoC-III-enriched lipoproteins are found [49][50][51]. Hepatic insulin resistance may contribute to a high production rate of VLDL because insulin reduces apoB synthesis and VLDL secretion in the liver [52,53]. Although insulin resistance is associated with high triglycerides, VLDL and TG concentrations can be similar in patients with widely divergent insulin sensitivity [54,55].…”