Fibroblast growth factor 15/19 expression, regulation, and function: An overview

Guthrie, Gregory; Vonderohe, Caitlin; Burrin, Douglas G.

doi:10.1016/j.mce.2022.111617

Cited by 20 publications

(26 citation statements)

References 163 publications

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“…bile acid synthesis is regulated by the intestinal FXR-FGF15 axis and local FXR signaling in the liver (23)(24)(25)(26)(27)(28)(29).…”

Section: Minocycline Causes a Sustained Disruption Of The Intestinal ...mentioning

confidence: 99%

“…The intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis is a gut-liver endocrine axis that suppresses hepatic bile acid synthesis to support systemic bile acid homeostasis (23)(24)(25)(26)(27)(28)(29). Primary bile acids are synthesized from cholesterol in the liver, conjugated with taurine or glycine, and excreted into the intestine, where the microbiota metabolizes them (23)(24)(25)(26)(27)(28)(29). Bile acids act as agonists or antagonists at the nuclear FXR, which intestinal enterocytes express at high levels (23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

“…Primary bile acids are synthesized from cholesterol in the liver, conjugated with taurine or glycine, and excreted into the intestine, where the microbiota metabolizes them (23)(24)(25)(26)(27)(28)(29). Bile acids act as agonists or antagonists at the nuclear FXR, which intestinal enterocytes express at high levels (23)(24)(25)(26)(27)(28)(29). Bile acid activation of enterocyte-FXR induces the production of intestinal FGF15 (rodent ortholog of human FGF19) (23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

“…Bile acids act as agonists or antagonists at the nuclear FXR, which intestinal enterocytes express at high levels (23)(24)(25)(26)(27)(28)(29). Bile acid activation of enterocyte-FXR induces the production of intestinal FGF15 (rodent ortholog of human FGF19) (23)(24)(25)(26)(27)(28)(29). Intestinal FGF15/19 is a hormonelike factor that signals at hepatocyte-fibroblast growth factor receptor 4 (FGFR4) to suppress cholesterol 7αhydroxylase (CYP7A1)-mediated liver bile acid synthesis and support systemic bile acid homeostasis (23)(24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

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Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice

et al. 2023

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Antibiotic-induced shifts in the indigenous gut microbiota influence normal skeletal maturation. Current theory implies that gut microbiota actions on bone occur through a direct gut-bone signaling axis. However, our prior work supports that a gut-liver signaling axis contributes to gut microbiota effects on bone. Purpose was to investigate the effects of minocycline, a systemic antibiotic treatment for adolescent acne, on pubertal/postpubertal skeletal maturation. Sex-matched specific-pathogen-free(SPF) and germ-free(GF) C57BL/6T mice were administered a clinically relevant minocycline dose from age 6-12 weeks. Minocycline caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation in SPF mice, but did not alter the skeletal phenotype in GF mice. Minocycline administration in SPF mice disrupted the intestinal farnesoid X receptor(FXR)-fibroblast growth factor 15(FGF15) axis, a gut-liver endocrine axis supporting systemic bile acid homeostasis. Minocyclinetreated SPF mice had increased serum conjugated bile acids that are FXR antagonists, suppressed osteoblast function, decreased bone mass, impaired bone microarchitecture and fracture resistance. Stimulating osteoblasts with the serum bile acid profile from minocycline-treated SPF mice recapitulated the suppressed osteogenic phenotype found in vivo, which was mediated through attenuated FXR-signaling. This work introduces bile acids as a novel mediator of gut-liver signaling actions contributing to gut microbiota effects on bone.

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“…bile acid synthesis is regulated by the intestinal FXR-FGF15 axis and local FXR signaling in the liver (23)(24)(25)(26)(27)(28)(29).…”

Section: Minocycline Causes a Sustained Disruption Of The Intestinal ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice

et al. 2023

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“…KLB, unlike Klotho, does not appear to have endocrine functions on its own. FGF19 plays a major role in bile acid homeostasis and liver metabolism ( Dolegowska et al, 2019 ; Guthrie et al, 2022 ). FGF21 is involved in regulating lipid metabolism, insulin secretion and glucose homeostasis ( Andersen et al, 2015 ; Bondurant and Potthoff, 2018 ; Dolegowska et al, 2019 ).…”

Section: β-Klothomentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Sarcopenia and frailty in inflammatory bowel disease: Emerging concepts and evidence

Neelam,

Sharma,

Sharma

2024

JGH Open

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Sarcopenia is a condition marked by progressive loss of skeletal muscle mass and function while frailty is a multidimensional concept characterized by diminished physiological reserve and increased vulnerability to stressors. Both of these were previously considered as related to aging and shown to impact the quality of life and carry prognostic significance. Emerging data show that both sarcopenia and frailty carry similar relevance in chronic illness. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and malnourishment, both of which contribute to the development of sarcopenia by increasing protein breakdown and reducing protein synthesis. The coexistence of frailty further compounds the clinical complexity of IBD patients. Published evidence suggests a bidirectional association with IBD contributing to muscle wasting, while the resultant sarcopenia and frailty could further exacerbate the disease course. Sarcopenia and frailty are independently associated with adverse outcomes, including hospitalizations, increased surgical interventions, and surgical complications. As therapeutic strategies for IBD evolve, understanding the nuanced relationship between inflammatory bowel disease, sarcopenia, and frailty is crucial for devising holistic management. Comprehensive care should encompass not only disease‐modifying therapies but also interventions targeting frailty and sarcopenia, as they have been shown to have a significant impact not only on the disease course but also on the quality of life. Future research could focus on further elucidating underlying mechanisms, simple screening strategies, and developing targeted interventions to improve the overall quality of life for individuals grappling with the complex interplay of IBD, sarcopenia, and frailty.

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Fibroblast growth factor 15/19 expression, regulation, and function: An overview

Cited by 20 publications

References 163 publications

Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice

Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Sarcopenia and frailty in inflammatory bowel disease: Emerging concepts and evidence

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