Abstract
Forkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets—very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)—on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.
Highlights
Forkhead O transcription factors (FOXOs) play a critical role in the integration of hormonal and nutritional signals for metabolic control[1]
It has been shown that diets containing excessive amount of fat, especially saturated fatty acids, remarkably increase the risk of obesity and nonalcoholic fatty liver disease (NAFLD)[27,28,29,30]
We have recently reported that FOXOs regulate both total cholesterol and low-density lipoprotein cholesterol[7,25]
Summary
Forkhead O transcription factors (FOXOs) play a critical role in the integration of hormonal and nutritional signals for metabolic control[1]. As a downstream mediator of insulin signaling, the activity of FOXOs is modulated by serine/threonine phosphorylation catalyzed by Akt and other kinases This insulin-mediated regulation has been implicated in the metabolic control during fasting and feeding cycles. As sirtuins are NAD-dependent enzymes, FOXOs have been shown to modulate sirtuin activities through control of expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD biosynthesis[8] Both SIRT1 and SIRT6 have been shown to inhibit lipogenesis and promote fatty acid oxidation in the liver[24]. FOXOs increase breakdown of lipid droplets through activation of the autophagy pathway as autophagy related 14 (ATG14) has been shown to be a direct target of FOXOs26 Both endogenous and exogenous factors can cause dysregulation of hepatic lipid homeostasis. To better understand the gene (notably FOXOs)-environment (different types of diets) interaction in the development of NAFLD, we set out to characterize wildtype (WT) and Foxo1/3/4 liver-specific triple knockout mice (LTKO) that were fed either regular chow, high-fat or moderately high-fat plus cholesterol diet
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