Updated: Oct 30
Some interesting research on a receptor (FXR/NR1H4) that supports the liver, bile, the bile salt export pump (BSEP/ABCB11) and Glut4 (what!) yep the same GLUT4 that modulates blood sugar.
Folks with compromised NR1H4, liver congestion, blood sugar issues, may find the below research interesting related to Reishi. However, mushrooms, like other things can also cause neuro over excitation, especially those with NMDA and or AHR receptor issues.
Equally as important , is that Reishi induced CYP7A1:).
"The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear receptor that is encoded by the NR1H4 gene in humans.
FXR is expressed at high levels in the liver and intestine. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer with RXR) and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes.
One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of small heterodimer partner (SHP), which then functions to inhibit transcription of the CYP7A1 gene. In this way, a negative feedback pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.
The absence of FXR in an FXR-/- mouse model led to increased bile acids in the liver, and the spontaneous development of liver tumors. Reducing the pool of bile acids in the FXR-/- mice by feeding the bile acid sequestering resin cholestyramine reduced the number and size of the malignant lesions.
FXR has also been found to be important in regulation of hepatic triglyceride levels. Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation. Studies have also shown the FXR to regulate the expression and activity of epithelial transport proteins involved in fluid homeostasis in the intestine, such as the cystic fibrosis transmembrane conductance regulator (CFTR).
Farnesoid X receptor has been shown to interact with:
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha and
Retinoid X receptor alpha.
"GLUT4, the main insulin-responsive glucose transporter, plays a critical role in maintaining systemic glucose homeostasis and is subject to complicated metabolic regulation. GLUT4 expression disorder might cause insulin resistance, and over-expression of GLUT4 has been confirmed to ameliorate diabetes. Here, we reported that farnesoid X receptor (FXR) and its agonist chenodeoxycholic acid (CDCA) could induce GLUT4 transcription in 3T3-L1 and HepG2 cells. Furthermore, CDCA could increase the GLUT4 protein amount in C57BL/6J mice sex-dependently. The following progressive 5'-deletion analysis and site-mutation investigation further suggested that FXR could induce GLUT4 expression through FXR response element (FXRE) in the GLUT4 promoter. EMSA and knock-down of retinoid X receptor (RXR) indicated that FXR binds to the GLUT4-FXRE as a monomer and RXR does not participate in the FXR stimulation of GLUT4 expression. In addition, we demonstrated that FXR does not interfere with insulin-induced GLUT4 translocation to plasma membrane. All these data thereby implied that FXR is a new transcription factor of GLUT4, further elucidating the potential role for FXR in glucose metabolism."
"Farnesoid X Receptor plays an important role in maintaining bile acid, cholesterol homeostasis and glucose metabolism. Here we investigated whether FXR is expressed by pancreatic β-cells and regulates insulin signaling in pancreatic β-cell line and human islets. We found that FXR activation induces positive regulatory effects on glucose-induced insulin transcription and secretion by genomic and non-genomic activities. Genomic effects of FXR activation relay on the induction of the glucose regulated transcription factor KLF11. Indeed, results from silencing experiments of KLF11 demonstrate that this transcription factor is essential for FXR activity on glucose-induced insulin gene transcription. In addition FXR regulates insulin secretion by non-genomic effects. Thus, activation of FXR in βTC6 cells increases Akt phosphorylation and translocation of the glucose transporter GLUT2 at plasma membrane, increasing the glucose uptake by these cells. In vivo experiments on Non Obese Diabetic (NOD) mice demonstrated that FXR activation delays development of signs of diabetes, hyperglycemia and glycosuria, by enhancing insulin secretion and by stimulating glucose uptake by the liver. These data established that an FXR-KLF11 regulated pathway has an essential role in the regulation of insulin transcription and secretion induced by glucose."
Reishi to the Rescue:
"Background/aims: Non-alcoholic fatty liver disease (NAFLD) encompasses a series of pathologic changes ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma. The purpose of this study was to determine whether ganoderma lucidum polysaccharide peptide (GLPP) has therapeutic effect on NAFLD.
Methods: Ob/ ob mouse model and ApoC3 transgenic mouse model were used for exploring the effect of GLPP on NAFLD. Key metabolic pathways and enzymes were identified by metabolomics combining with KEGG and PIUmet analyses and key enzymes were detected by Western blot. Hepatosteatosis models of HepG2 cells and primary hepatocytes were used to further confirm the therapeutic effect of GLPP on NAFLD.
Results: GLPP administrated for a month alleviated hepatosteatosis, dyslipidemia, liver dysfunction and liver insulin resistance. Pathways of glycerophospholipid metabolism, fatty acid metabolism and primary bile acid biosynthesis were involved in the therapeutic effect of GLPP on NAFLD. Detection of key enzymes revealed that GLPP reversed low expression of CYP7A1, CYP8B1, FXR, SHP and high expression of FGFR4 in ob/ob mice and ApoC3 mice. Besides, GLPP inhibited fatty acid synthesis by reducing the expression of SREBP1c, FAS and ACC via a FXR-SHP dependent mechanism. Additionally, GLPP reduced the accumulation of lipid droplets and the content of TG in HepG2 cells and primary hepatocytes induced by oleic acid and palmitic acid.
Conclusion: GLPP significantly improves NAFLD via regulating bile acid synthesis dependent on FXR-SHP/FGF pathway, which finally inhibits fatty acid synthesis, indicating that GLPP might be developed as a therapeutic drug for NAFLD."
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Farnesoid X Receptor Induces GLUT4 Expression Through FXR Response Element in the GLUT4 Promoter. Hong Shen; et. al. Cellular Physiology and Biochemistry (2008) 22 (1-4): 001–014. https://doi.org/10.1159/000149779. RESEARCH ARTICLES| JULY 25 2008
The bile acid sensor FXR regulates insulin transcription and secretion. Barbara Renga a, Andrea Mencarelli a, et. al. https://doi.org/10.1016/j.bbadis.2010.01.002. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. Volume 1802, Issue 3, March 2010, Pages 363-372
Ganoderma Lucidum Polysaccharide Peptide Alleviates Hepatoteatosis via Modulating Bile Acid Metabolism Dependent on FXR-SHP/FGF. Dandan Zhong 1, Zhengwei Xie, et. al. Cell Physiol Biochem. . 2018;49(3):1163-1179. doi: 10.1159/000493297. Epub 2018 Sep 7. PMID: 30196282. DOI: 10.1159/000493297