The Prospective Association Of Fibroblast Growth Factor 21 With Nonalcoholic Fatty Liver Disease And The Molecular Mechanism Of Regulation Of Its Co-receptor

Fibroblast Growth Factor 21(FGF21), a hormone mainly secreced by liver,has recently been shown to have beneficial role on glucose and lipid metabolism and insulin sensitivity in animal models. Serum FGF21 level is associated with the degree of steatosis, and it is possible that FGF21 maybe the serum biomarker for nonalcoholic fatty liver disease(NAFLD). However the prospective role of FGF21 in diagose of NAFLD is still largely unknown. β-Klotho, a co-receptor for FGF21, is required for FGF21 effect on the metabolism and growth. The association of β-Klotho and endoplasmic reticulum stress with NAFLD is far from being fully understood. This study investigated the prospective association of FGF21 with NAFLD and the molecular mechanism of regulation of its co-receptor by two parts.1. The prospective Association of Fibroblast Growth Factor 21 with Nonalcoholic Fatty Liver DiseaseObjective: This study investigated the prospective association of FGF21 with NAFLD development in a 3-year prospective study involving a population-based cohort Chinese subjects.Methods: In 2007-2008, one population-based surveys were conducted in Shanghai to investigate the prevalence of metabolic disorders. These surveys obtained height, waist circumference, and weight measurements for Chinese adults aged between 20 and 74 years who lived in urban communities. 808 participants were recruited,and 660 participants completed baseline and follow-up studies. Serum FGF21 levels at baseline and follow-up were measured using an enzymelinked immunosorbent assay(Elisa). Independent predictors of NAFLD development were identified using multiple logistic regressions. The predicting accuracy of the models was evaluated using area under the receiver-operating characteristic(ROC) curves(AUCs).Result: NAFLD incidence rate at this 3-year follow-up was 17.87%(79/442)(95% CI 14.30–21.44%). The annual incidence rate was 6.0%. In subjects who had progressed to NAFLD, the baseline FGF21 concentration(319.12 pg/ml [172.65, 518.78]) was significantly higher than that in subjects who did not develop NAFLD(199.10 pg/ml [123.56, 322.80])(p <0.001). At follow-up, significant increase of FGF21 level was observed in those subjects who developed NAFLD(p <0.05). Baseline FGF21 was an independent predictor of NAFLD(OR: 7.102 [95% CI 2.488–20.270]; p <0.001), together with body mass index(BMI)(OR: 1.489 [95% CI 1.310– 1.691]; p <0.001). The ROC-AUC was 0.816(95% CI 0.766– 0.867) for the FGF21 Model, which was calculated with FGF21 and BMI. FGF21 Model <0.13 can be used to rule out(sensitivity = 85.71%, negative likelihood ratio = 0.23) and P≥0.30 can be rule in(specificity = 86.34%, positive likelihood ratio =3.66) ultrasonography-diagnosed NAFLD after 3 years.Conclusion: High serum FGF21 concentration was an independent predictor of nonalcoholic fatty liver disease in humans. The FGF21 Model and its cut-offs may be useful for early diagnosis and intervention of nonalcoholic fatty liver disease.2. Molecular Mechanism of regulation of Co-receptor of Fibroblast Growth Factor 21 in Nonalcoholic Fatty Liver DiseaseObjective: This study was to investigate the association between co-receptor of FGF21 and endoplasmic reticulum stress in NAFLD. And it aimed to figure out the mechanism how endoplasmic reticulum stress regulated co-receptor of FGF21.Method: To detect β-Klotho and CHOP in the liver of different obesity animal model and NAFLD patients. β-Klotho m RNA expression and protein levels were examined in haptoma cells and C57BL/6J mice were treated with tunicamycin and thapsigargin. The mechanism study wan investigated through si RNA knockingdown.Result: Elevation of β-Klotho protein expression in diet-induced obese mice and human patients was associated with increased endoplasmic reticulum(ER) stress. In vivo study indicated that administration of the ER stressor tunicamycin in mice led to increased expression of β-Klotho in the liver. In addition, ATF4 signaling pathway was essential for mediating the effect of ER stress on β-Klotho expression. And Overexpression of β-Klotho was in return to inhibit ER stress.Conclusion: These findings demonstrate a link of ER stress with up-regulation of hepatic β-Klotho expression and the molecular mechanism underlying ER stressregulated FGF21 signaling.