Browsing by Subject "Fibroblast Growth Factors"
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Item The Physiology and Pharmacology of FGF21 in the Exocrine Pancreas(2019-04-12) Hernandez, Genaro; Scherer, Philipp; Mangelsdorf, David J.; Kliewer, Steven A.; Elmquist, Joel; Takahashi, JosephThe exocrine pancreas comprises about 98% of the total pancreatic tissue. Its main function is the synthesis and secretion of digestive enzymes in order to facilitate nutrient absorption upon feeding. This function is mainly carried by acinar cells that require strict regulation of protein processing and stress-related pathways such as the integrated stress response pathway (ISR). Genetic, chemical or traumatic events can trigger an inflammatory response in the pancreas known as pancreatitis with prolonged ISR activation. In the pancreas, fibroblast growth factor 21 (FGF21) is highly expressed, induced by feeding and acts in an autocrine/paracrine fashion. The pancreas also expresses the FGFR1/beta-klotho receptor complex that FGF21 binds to elicit downstream signaling. The physiological function of FGF21 in the exocrine pancreas is to stimulate digestive enzyme secretion by triggering intracellular calcium release through FGFR1/beta-klotho-PLCgamma-IP3R; without affecting protein synthesis on acinar cells. The effect of FGF21 on secretion results in lower levels of ISR activation by decreasing intracellular protein load. However, endogenous FGF21 is downregulated in pancreatitis, which leads to increased inflammation and overall pancreatic damage. Given that pancreatitis is an FGF21-deficient state, it can be ameliorated by therapeutically administering recombinant FGF21. Furthermore, the therapeutic effect of FGF21 is dependent on the expression of beta-klotho in acinar cells. The cause of this FGF21 deficit is the competitive binding of the transcriptional repressor ATF3 that displaces the FGF21-inducing transcription factor ATF4 from the AARE1 response element in the FGF21 promoter of acinar cells. Since ATF3 is induced by ISR activation in pancreatitis, therapeutic inhibition of the ISR is also effective but requires endogenous FGF21. Moreover, FGF21 is therapeutically effective in different types of pancreatitis such as alcohol-induced pancreatitis or endoscopic retrograde cholangiopancreatography-induced pancreatitis. These findings are supported by evidence that in patients with pancreatitis FGF21 and ATF4 are lost, whereas ATF3 is upregulated. Thus, under physiological conditions such as feeding FGF21 maintains protein homeostasis by acting as an autocrine/paracrine secretagogue but it is downregulated in pancreatitis. Pharmacologically, FGF21 is a promising drug candidate for the treatment of pancreatitis.Item Understanding the Molecular Basis for FGF15/19 and FGF21 Actions on Energy Homeostasis(2012-07-09) Boney-Montoya, Jamie; Kliewer, Steven A.Insulin and glucagon have long been known to play essential roles in controlling energy balance during the fed and fasted states, respectively. Recently, additional metabolic hormones have been discovered within a subfamily of the fibroblast growth factor superfamily. The FGF15/19 subfamily is composed of atypical FGFs lacking the heparin-binding domain, which enables them to act in an endocrine fashion by diffusing away from their tissues of origin. They signal through cell-surface receptors complexed with β-Klotho, a membrane-spanning protein, to mediate signaling cascades that lead to physiological responses. One member, FGF19, causes reduced glucose and insulin levels with enhanced insulin sensitivity when expressed in transgenic mice. Another member, FGF21, has been shown to act as an insulin sensitizer pharmacologically by improving glucose tolerance and reducing insulin. The prevalence of metabolic disorders (e.g. type 2 diabetes) in today’s society has led to the investigation of these two endocrine FGFs for use in a clinical setting. However, the mechanisms underlying these responses have not been characterized. To elucidate the mechanisms utilized by FGF15/19, we used several animal models to show a role for FGF15/19 in regulating hepatic glucose production. Like insulin, FGF15/19 represses gluconeogenesis. Specifically, FGF15/19 inhibits expression of the transcriptional coactivator PGC1α, a key regulator of gluconeogenic gene expression. The repressive effect of FGF15/19 on gluconeogenic gene expression is lost when PGC1α is overexpressed. FGF15/19 causes the dephosphorylation and inactivation of the transcription factor CREB, thereby blunting its ability to bind and induce the PGC1α promoter. The results demonstrated that FGF15/19 works subsequent to insulin as a postprandial regulator of gluconeogenesis through inhibition of the CREB/ PGC1α pathway. To fully understand the effects of FGF21, we began studying the downstream kinase signaling cascades and the protein substrates affected by this hormone. Utilizing stable isotope labeling of amino acids in cell culture (SILAC), an unbiased phosphoproteomic profile was obtained of potential FGF21 targets in rat H4IIE hepatoma cells. One of the most highly regulated targets was FetuinA, which was dephosphorylated by FGF21 treatment. FetuinA is an inhibitor of insulin receptor signaling and the FetuinA knockout mouse exhibits aberrant glucose homeostatsis. Our in vitro data suggested a relationship between FGF21 and FetuinA in regulating insulin sensitivity but further exploration lead to the conclusion that FGF21 was not directly regulating FetuinA in vivo. Taken together, the important role of FGF15/19 and FGF21 in regulating carbohydrate metabolism as well as their pharmacological actions makes them attractive drug candidates for metabolic diseases. However, further study will be required to determine their molecular mechanisms more completely and their long-term efficacy in the clinic.Item [UT Southwestern Medical Center News](2011-03-24) Bolles, DebbieItem [UT Southwestern Medical Center News](2012-02-06) Bolles, DebbieItem [UT Southwestern Medical Center News](2007-06-05) Despres, CliffItem [UT Southwestern Medical Center News](2012-10-15) Wormser, Deborah