FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver

Huang, Xinqiang; Yang, Chao; Luo, Yongde; Jin, Chengliu; Wang, Fen; McKeehan, Wallace L.

doi:10.2337/db07-0648

Cited by 125 publications

(129 citation statements)

References 55 publications

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“…One is tempted to ascribe the repression of cholesterol 7 ␣ hydroxylase in the current studies to FGF19 signaling via its hepatic receptors and intestinal specifi c FGF19 gene activation may provide a mechanistic explanation for plasma lipid lowering effects. Recent genetic studies in mice suggest that hepatocyte FGFR4 plays an essential role in systemic lipid homeostasis, providing protection against hyperlipidemia and hypercholesterolemia to the detriment of liver lipid accumulation ( 42 ). However, our data indicates that several LXR ligands can activate human FGF19 in vitro and two of these (GW3965 and WAY-254011) ligands actually raised LDLc in vivo.…”

Section: Note Added In Proofcontrasting

confidence: 45%

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

Quinet¹,

Basso²,

Halpern³

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words cynomolgus monkey • dyslipidemia • fi broblast growth factor 19 • hypertriglyceridemiaAtherosclerosis is the major cause of cardiovascular disease and its incidence is on the rise due to its tight relationship to obesity and diabetes. Therapeutic interventions targeted at reducing elevated plasma low-density lipoprotein cholesterol (LDLc), the primary risk factor for development of atherosclerosis, do not eliminate cardiovascular risk particularly in several high-risk subpopulations. The statin class of drugs achieve dramatic reductions in LDLc yet reduce heart attack risk only 33% per 1.5 mmol/L reduction in LDL ( 1 ). As statins primarily limit disease progression through the inhibition of endogenous cholesterol synthesis, newer treatment modalities directed at reversing established atherosclerotic plaque are likely to provide additional benefi t and can have important clinical implications for disease management. This is exemplifi ed by the exploratory clinical studies targeting the enhancement of high-density lipoprotein ( 2 ). In this study, intravenous

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Section: Note Added In Proofcontrasting

confidence: 45%

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

Quinet¹,

Basso²,

Halpern³

et al. 2009

Journal of Lipid Research

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“…60), growth factor signaling through FGFR4 may play an important role in hepatic insulin action. In support of this idea, FGFR4 knock-out mice have impaired glucose tolerance (67), and transgenic expression of FGF19 reverses diabetes in the leptin-deficient ob/ob mouse (68).…”

Section: Discussionmentioning

confidence: 74%

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7␣ hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.Hepatic cholesterol is converted to bile acids, secreted into the gallbladder, and during a meal is released into the small intestine to enhance digestion and absorption of dietary lipids and fat-soluble vitamins. The majority of the bile acid pool (95%) is recycled back to the liver, whereas the remaining 5% is eliminated through fecal excretion (1, 2). This is an important route for the elimination of excess cholesterol and underscores the importance that bile acids play in regulating mammalian cholesterol metabolism. The initial and rate-controlling step in the classic pathway for cholesterol conversion into bile acids is catalyzed by cholesterol 7␣-hydroxylase (CYP7A1).2 CYP7A1 regulation is primarily transcriptional, and expression of its gene is dynamically regulated by hormones and metabolites (2-6). Importantly, bile acids themselves regulate CYP7A1 gene expression through a multicomponent negative feedback pathway. One of the molecular pathways for bile acid regulation is initiated by the activation of the farnesoid X receptor (FXR) responding directly to bile acid agonists (7). Ligand-activated FXR directly binds to a site in the promoter for the small heterodimer partner (SHP) gene and induces expression of SHP mRNA (8, 9). The translated SHP protein lacks the signature nuclear receptor zinc finger DNA binding domain but uses its conserved dimerization motif to form protein-protein contacts with DNA bound activators, usually other nuclear receptors, to inhibit or interfere with their activation potential (10, 11).The first identified target for SHP repression was the CYP7A1 promoter, and SHP was proposed to interfere with activation by the DNA-bound monomeric liver receptor homologue 1 (LRH-1) nucl...

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“…Although initially thought to act primarily via FGFR4 receptors in the liver, the antidiabetic effects of FGF19 appear to involve a different FGF receptor subtype, because they are preserved in FGFR4-deficient mice (9). Instead, several findings implicate FGFR1 in this effect.…”

Section: Introductionmentioning

confidence: 59%

FGF19 action in the brain induces insulin-independent glucose lowering

Morton¹,

Matsen²,

Bracy³

et al. 2013

J. Clin. Invest.

193

183

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Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain's capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal.

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FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver

Cited by 125 publications

References 55 publications

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

FGF19 action in the brain induces insulin-independent glucose lowering

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