Hepatic FoxO1 Ablation Exacerbates Lipid Abnormalities during Hyperglycemia

Abstract

Patients with diabetes suffer disproportionately from impaired lipid metabolism and cardiovascular disease, but the relevant roles of insulin resistance and hyperglycemia in these processes are unclear. Transcription factor FoxO1 is regulated dually by insulin and nutrients. In this study, we addressed the hypothesis that, in addition to its established role to regulate hepatic glucose production, FoxO1 controls aspects of lipid metabolism in the diabetic liver. Mice with a liver-specific deletion of FoxO1 (L-FoxO1) and their control littermates were rendered hyperglycemic by streptozotocin administration. Subsequently, we monitored serum lipids, liver VLDL secretion, and hepatic expression of genes related to lipid metabolism. Hepatic FoxO1 ablation resulted in increased VLDL secretion, increased cholesterol, and increased plasma free fatty acids, three hallmarks of the diabetic state. L-FoxO1 mice expressed increased levels of SREBP-2 and FGF21 without affecting lipogenic genes. We propose that FoxO1 fine tunes lipolysis through its actions on FGF21 and that hepatic FoxO1 ablation increases availability of substrates for hepatic triglyceride and cholesterol synthesis and VLDL secretion. The implications of these findings are that FoxO1 protects against excessive hepatic lipid production during hyperglycemia and that its inhibition by intensive insulin treatment may exacerbate paradoxically the lipid abnormalities of diabetes.Alterations of lipid metabolism are an integral part of the metabolic syndrome and diabetes and can lead to the development of cardiovascular diseases (1). Individuals with type 2 diabetes have a 2-4-fold increase in their lifetime risk of developing cardiovascular diseases, and heart disease is the leading cause of death among diabetics (2). The primary abnormalities of lipid metabolism in diabetes are increased free fatty acid (FFA) levels, and increased plasma triglyceride (TG) 2 and cholesterol in atherogenic lipoprotein fractions, due in part to excessive secretion of very low density lipoproteins (VLDL) by the liver (3). However, it is unclear how insulin resistance and diabetes affect the development of these defects. Two mutually nonexclusive causes have been proposed: insulin resistance and hyperglycemia. Delineating the relative roles of these two states has been difficult because they typically coexist, although increased TG and VLDL can be observed in insulin-resistant humans long before the development of hyperglycemia (4). Furthermore, most prospective studies indicate that tight glucose control has little benefit, or possible untoward effects, on macrovascular complications of diabetes (5). Thus, insulin resistance appears to have an independent effect on the development of the lipid abnormalities that lead to cardiovascular disease.An early step in the development of atherosclerosis is increased production of hepatic TG and low density lipoproteins (namely, VLDL) (6). But the mechanism by which insulin resistance affects hepatic lipid metabolism remains elusive. In recent y...

Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6

“…The hepatic levels of Sirt6 mRNA and protein were decreased plasma cholesterol, LKO1 mice do not exhibit a significant change in circulated cholesterol ( 14,62,63 ). However, under the hyperglycemic condition induced by streptozotocin injections, hepatic FoxO1 defi ciency leads to elevated serum cholesterol and a modest increase in Srebp2 mRNA levels in the liver ( 13 ). These results are in line with our observation that FoxO1 is not a major player in hepatic cholesterol biosynthesis under physiological conditions.…”

“…The liver plays a critical role in cholesterol homeostasis, including de novo biosynthesis, effl ux, and conversion to bile acids ( 1,4,(7)(8)(9). Several transcription factors in the liver have been linked to cholesterol regulation, including SREBP-2, SREBP-1a, liver X receptor, farnesoid X receptor, and forkhead box O (FoxO) transcription factors ( 3,4,(9)(10)(11)(12)(13)(14)(15). With regard to FoxOs, the mechanisms for cholesterol regulation are not well understood ( 9,(13)(14)(15)(16)(17).…”

“…Several transcription factors in the liver have been linked to cholesterol regulation, including SREBP-2, SREBP-1a, liver X receptor, farnesoid X receptor, and forkhead box O (FoxO) transcription factors ( 3,4,(9)(10)(11)(12)(13)(14)(15). With regard to FoxOs, the mechanisms for cholesterol regulation are not well understood ( 9,(13)(14)(15)(16)(17). Some of these factors can also be modulated by posttranslational modifi cations, for instance, deacetylation by an NAD + -dependent deacetylase sirtuin (Sirt)1 (18)(19)(20).…”

Insulin Regulates Retinol Dehydrogenase Expression and All-trans-retinoic Acid Biosynthesis through FoxO1

“…A liver-specific FoxO1-null mouse crossed with an insulin receptor-null mouse has reduced glucose production and lacks the neonatal diabetes and hepatosteatosis that occur in insulin receptor-null mice (63). Liver-specific FoxO1-null mice treated with the ␤-cell toxin streptozotocin, have elevated VLDL secretion, cholesterol, and plasma-free fatty acids (65).…”

Water Extracts of Immature <i>Rubus coreanus</i> Regulate Lipid Metabolism in Liver Cells

“…23) Similarly, p-FoXo-1 tunes up lipolysis through its action on fibroblast growth factor (FGF21). 23) In our study, RCE treatment upregulated the expression of p-FoXo-1 in a dose dependent manner, indicating lipolysis in HepG2 cells, thus lowering of cholesterol and triglyceride biosynthesis.…”