Silencing of the <i>Fibroblast growth factor 21</i> gene is an underlying cause of acinar cell injury in mice lacking MIST1

Johnson, C. L.; Mehmood, Rashid; Laing, Scott W; Stepniak, Camilla V; Kharitonenkov, Alexei; Pin, Christopher L.

doi:10.1152/ajpendo.00559.2013

Cited by 32 publications

(30 citation statements)

References 55 publications

(81 reference statements)

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“…Our findings are consistent with reports showing that pancreatic FGF21 expression increases in mice with cerulein-induced pancreatitis [10, 11]. To our knowledge, only one other study has analyzed FGF21 levels in human acute pancreatitis [14].…”

Section: Discussionsupporting

confidence: 93%

“…While FGF21 expression is highest in the pancreas[9], few studies have addressed the possible role of FGF21 in this tissue. In mice, increased pancreatic FGF21 is seen with cerulein-induced pancreatic injury, with more severe injury observed in mice lacking FGF21 [10, 11]. To assess the possibility that FGF21 is released from the pancreas during acute injury in humans, we measured circulating FGF21 in subjects with acute pancreatitis over the course of their disease.…”

Section: Introductionmentioning

confidence: 99%

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Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis

et al. 2016

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BackgroundThe metabolic regulator Fibroblast Growth Factor 21 (FGF21) is highly expressed in the acinar pancreas, but its role in pancreatic function is obscure. It appears to play a protective role in acute experimental pancreatitis in mice. The aim of this study was to define an association between FGF21 and the course and resolution of acute pancreatitis in humans.Methods and Principal FindingsTwenty five subjects with acute pancreatitis admitted from May to September 2012 to the Beth Israel Deaconess Medical Center (BIDMC) were analyzed. Serial serum samples were collected throughout hospitalization and analyzed for FGF21 levels by ELISA. Twenty healthy subjects sampled three times over a four week period were used as controls. We found that, in patients with pancreatitis, serum FGF21 rises significantly and peaks four to six days after the maximum lipase level, before slowly declining. Maximum FGF21 levels were significantly greater than baseline levels for acute pancreatitis subjects (1733 vs. 638 pg/mL, P = 0.003). This maximum value was significantly greater than the highest value observed for our control subjects (1733 vs. 322 pg/mL, P = 0.0002). The ratio of active to total FGF21 did not change during the course of the disease (42.5% vs. 44.4%, P = 0.58). Fold increases in FGF21 were significantly greater in acute pancreatitis subjects than the fold difference seen in healthy subjects (4.7 vs. 2.0, P = 0.01). Higher fold changes were also seen in severe compared to mild pancreatitis (18.2 vs. 4.4, P = 0.01). The timing of maximum FGF21 levels correlated with day of successful return to oral intake (R2 = 0.21, P = 0.04).ConclusionsOur results demonstrate that serum FGF21 rises significantly in humans with acute pancreatitis. The pancreas may be contributing to increased FGF21 levels following injury and FGF21 may play a role in the recovery process.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis

et al. 2016

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“…Fgf21 -knockout (KO) mice have a heightened susceptibility to pancreatic inflammation and injury caused by the potent cholecystokinin (CCK) analog cerulein (Johnson et al, 2009). Likewise, mice lacking the pancreatic transcription factor MIST1 are susceptible to pancreatitis due to silencing of the Fgf21 gene (Johnson et al, 2014). Conversely, FGF21 overexpression protects the pancreas against inflammation and injury in both cerulein-treated and MIST1-knockout mice (Johnson et al, 2014; Johnson et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

FGF21 Is an Exocrine Pancreas Secretagogue

et al. 2017

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Summary The metabolic stress hormone FGF21 is highly expressed in exocrine pancreas, where its levels are increased by refeeding and chemically-induced pancreatitis. However, its function in the exocrine pancreas remains unknown. Here, we show that FGF21 stimulates digestive enzyme secretion from pancreatic acinar cells through an autocrine/paracrine mechanism that requires signaling through a tyrosine kinase receptor complex composed of an FGF receptor and β-Klotho. Mice lacking FGF21 accumulate zymogen granules and are susceptible to pancreatic ER stress, an effect that is reversed by administration of recombinant FGF21. Mice carrying an acinar cell-specific deletion of β-Klotho also accumulate zymogen granules, but are refractory to FGF21-stimulated secretion. Like the classical post-prandial secretagogue, cholecystokinin (CCK), FGF21 triggers intracellular calcium release via PLC-IP3R signaling. However, unlike CCK, FGF21 does not induce protein synthesis, thereby preventing protein accumulation. Thus, pancreatic FGF21 is a digestive enzyme secretagogue whose physiologic function is to maintain acinar cell proteostasis.

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“…Importantly, pancreatic inflammation and fibrosis were increased in Fgf21 K/K mice compared to control mice and, conversely, were decreased in Fgf21 transgenic mice (Johnson et al 2009). Furthermore, FGF21 expression was markedly reduced in acinar cells of Mist1 knockout mice showing early events of pancreatitis such as the premature activation of digestive enzymes and acinar disorganization (Johnson et al 2014). These results suggest that FGF21 induction may be an adaptive mechanism to protect the development and progression of pancreatitis.…”

Section: Fgf21 and Pancreatitismentioning

confidence: 79%

“…Several studies have shown that FGF21 modulates the development and progression of pancreatitis, a known risk factor for pancreatic cancer (Johnson et al 2009(Johnson et al , 2014. In mice with cerulein-induced acute pancreatitis, FGF21 expression was increased in acinar cells but not in islet cells.…”

Section: Fgf21 and Pancreatitismentioning

confidence: 99%

FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

Kim¹,

Lee²

2015

Journal of Endocrinology

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Most hormones secreted from specific organs of the body in response to diverse stimuli contribute to the homeostasis of the whole organism. Fibroblast growth factor 21 (FGF21), a hormone induced by a variety of environmental or metabolic stimuli, plays a crucial role in the adaptive response to these stressful conditions. In addition to its role as a stress hormone, FGF21 appears to function as a mediator of the therapeutic effects of currently available drugs and those under development for treatment of metabolic diseases. In this review, we highlight molecular mechanisms and the functional importance of FGF21 induction in response to diverse stress conditions such as changes of nutritional status, cold exposure, and exercise. In addition, we describe recent findings regarding the role of FGF21 in the pathogenesis and treatment of diabetes associated with obesity, liver diseases, pancreatitis, muscle atrophy, atherosclerosis, cardiac hypertrophy, and diabetic nephropathy. Finally, we discuss the current understanding of the actions of FGF21 as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagonlike peptide 1 analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid.

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Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1

Abstract: Johnson CL, Mehmood R, Laing SW, Stepniak CV, Kharitonenkov A, Pin CL. Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1. Am

Cited by 32 publications

References 55 publications

Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis

Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis

FGF21 Is an Exocrine Pancreas Secretagogue

FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

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