https://www.hal.inserm.fr/inserm-02108766/document

Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease.

The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.

Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23

Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.

/pdf/fgfr-inhibitors-effects-on-cancer-cells-tumor-2wjw1o3wh7.pdf

FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review)

Effect of ethanol on lipid metabolism

http://diposit.ub.edu/dspace/bitstream/2445/167638/1/691908.pdf

Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins

https://www.jbc.org/content/289/44/30470.full.pdf

Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions

Changes in the human skeleton can result from DNA variants that are transmitted from parent to child via the normal meiotic processes. Genetic diseases can be inherited in rare disorders through Mendelian (single-gene) fashion via defined modes of inheritance, or through DNA changes that are much more common in the human population, and can consist of variants in multiple genes. Variants contributing to Mendelian traits usually produce large effects on gene function, with a single variant often being solely responsible for the observed bone phenotype. In contrast, in common diseases containing a heritable component, each genetic variant typically has a small effect, with the sum of these effects producing the observed phenotype. Once a gene or variant is found that links to a Mendelian disorder or to a structural or functional bone phenotype, these variants can be studied in vivo through the use of transgenic mouse models. The techniques and theory underlying isolating genetic changes that relate to diseases of bone, as well as the use of animal models for understanding bone function and targeted therapeutics, will be discussed in this chapter.

Skeletal Genetics: From Gene Identification to Murine Models of Disease

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Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions

Skeletal Genetics: From Gene Identification to Murine Models of Disease