Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP regulation by forkhead box O1 (FoxO1), a transcription factor that plays a key role in hepatic insulin signaling. In HepG2 cells, MTP expression was induced by FoxO1 and inhibited by exposure to insulin. This effect correlated with the ability of FoxO1 to bind and stimulate MTP promoter activity. Deletion or mutation of the FoxO1 target site within the MTP promoter disabled FoxO1 binding and resulted in abolition of insulin-dependent regulation of MTP expression. We generated mice that expressed a constitutively active FoxO1 transgene and found that increased FoxO1 activity was associated with enhanced MTP expression, augmented VLDL production, and elevated plasma triglyceride levels. In contrast, RNAi-mediated silencing of hepatic FoxO1 was associated with reduced MTP and VLDL production in adult mice. Furthermore, we found that hepatic FoxO1 abundance and MTP production were increased in mice with abnormal triglyceride metabolism. These data suggest that FoxO1 mediates insulin regulation of MTP production and that augmented MTP levels may be a causative factor for VLDL overproduction and hypertriglyceridemia in diabetes.

FoxO1 plays an important role in mediating the effect of insulin on hepatic metabolism. Increased FoxO1 activity is associated with reduced ability of insulin to regulate hepatic glucose production. However, the underlying mechanism and physiology remain unknown. We studied the effect of FoxO1 on the ability of insulin to regulate hepatic metabolism in normal vs. insulin-resistant liver under fed and fasting conditions. FoxO1 gain of function, as a result of adenovirus-mediated or transgenic expression, augmented hepatic gluconeogenesis, accompanied by decreased glycogen content and increased fat deposition in liver. Mice with excessive FoxO1 activity exhibited impaired glucose tolerance. Conversely, FoxO1 loss of function, caused by hepatic production of its dominant-negative variant, suppressed hepatic gluconeogenesis, resulting in enhanced glucose disposal and improved insulin sensitivity in db/db mice. FoxO1 expression becomes deregulated, culminating in increased nuclear localization and accounting for its increased transcription activity in livers of both high fat-induced obese mice and diabetic db/db mice. Increased FoxO1 activity resulted in up-regulation of hepatic peroxisome proliferator-activated receptor-gamma coactivator-1beta, fatty acid synthase, and acetyl CoA carboxylase expression, accounting for increased hepatic fat infiltration. These data indicate that hepatic FoxO1 deregulation impairs the ability of insulin to regulate hepatic metabolism, contributing to the development of hepatic steatosis and abnormal metabolism in diabetes.

.-High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that highfructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-␥ coactivator-1␤ and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-␣ (PPAR␣). PPAR␣ physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPAR␣ constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.hypertriglyceridemia; forkhead box O1; peroxisome proliferator-activated receptor-␣; apolipoprotein C-III; very-low-density lipoproteintriglyceride; microsomal triglyceride transfer protein HYPERTRIGLYCERIDEMIA IS CHARACTERIZED by increased production of very-low-density lipoprotein (VLDL) and/or decreased clearance of triglyceride (TG)-rich particles (4). Due to its proatherogenic profile, hypertriglyceridemia is a major contributing factor for the pathogenesis of atherosclerosis and coronary artery disease in obesity and type 2 diabetes. While the pathophysiology of hypertriglyceridemia is poorly understood, its close association with visceral adiposity and type 2 diabetes implicates insulin resistance as a causative factor in the development of hypertriglyceridemia (5,12,22,29,42). However, the molecular events that link insulin resistance to the pathogenesis of hypertriglyceridemia remain elusive.An important player in plasma VLDL-TG metabolism is apolipoprotein C-III (apoC-III). It functions as an inhibitor of lipoprotein lipase and hepatic lipase, playing a pivotal role in the hydrolysis and clearance of TG-rich particles such as VLDL-TG and chylomicrons (27,36,51,53). Elevated plasma apoC-III levels are associated with impaired clearance of TG-rich particles, leading to the accumulation of TG-rich lipoprotein remnants in plasma and the development of hypertriglyceridemia.Our recent data indicate that forkhead box O1 (FoxO1), a nuclear transcription factor known to be a mediator of insulin signaling, plays an important role in hepatic regulation of apoC-III. FoxO1 stimulates hepatic apoC-III expression, which is counteracted by insulin (2). Elevated FoxO1 production in liver augments hepatic apoC-III expression, r...

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.

Ca2؉ may trigger programmed cell death (apoptosis) and regulate death-specific enzymes. Therefore, the development of strategies to control Ca 2؉ homeostasis may represent a potential approach to prevent or enhance cell apoptosis. To test this hypothesis, the plasma membrane Na/Ca exchanger (NCX1.7 isoform) was stably overexpressed in insulin-secreting tumoral cells. homeostasis that could, on the contrary, prevent the process of apoptosis that mediates, in part, ␤-cell autoimmune destruction in type 1 diabetes. NCX1.7 overexpression increased apoptosis induced by endoplasmic reticulum (ER) Ca