| The metabolic syndrome (MS) is a cluster of interrelated common clinicaldisorders, including obesity, insulin resistance, glucose intolerance, hypertension anddyslipidemia. As the common initiator and core factor of MS, obesity especiallyabdominal obesity is related closely to its occurrence and development. Non-alcoholicfatty liver disease (NAFLD) is a clinical pathogenic syndrome, which is trigged bymultiple factors and characterized by fatty degeneration of liver cells and lipidaccumulation. NAFLD is the most common cause of chronic liver disease and oftenaccompanied by a series of metabolic disorders, such as obesity especially abdominalobesity, type2diabetes, hypertension and dyslipidemia. However, the role of NAFLDin metabolic disorders is still not clear. Recently, adiponectin is found to be animportant factor involved in regulation of obesity, while adaptor protein binding toadiponectin receptor (APPL2) has an essential function in mediating adiponectinsignaling transduction; fibroblast growth factor21(FGF21) is also closely associatedwith obesity and NAFLD. In the view of close association of abdominal obesity andNAFLD, this study focuses on the associations and molecular mechanism of APPL2and FGF21with the abdominal obesity and NAFLD. The study is divided into threeparts, the contents and main findings are as follows:1. Associations between APPL2genetic variants and abdominal obesity andchronic liver injure in Han Chinese population with normal glucose toleranceAPPL1and APPL2are two adaptor proteins, which can mediate adiponectin signalingvia binding to N terminus of adiponectin receptors (AdipoR1and AdipoR2). Genes encoding adiponectin and adiponectin receptors contribute to insulin resistance andthe risk of obesity, and genetic variants of APPL1are associated with body fatdistribution. However, the associations between genetic variations of APPL2andmetabolic diseases such as obesity and NAFLD remain unknown. In the current study,we aimed to explore the impacts of APPL2genetic variants on abdominal obesity andchronic liver injure in Han Chinese population with normal glucose tolerance. Werecruited1,806adult individuals from Shanghai and all were with normal glucoseregulation (NGT). Obesity-related anthropometric parameters were measured,including height, weight, waist circumference, hip circumference. BMI and waist-hipratio (WHR) were calculated. We selected and genotyped six single nucleotidepolymorphisms (SNPs) in APPL2(rs2272495, rs10861360, rs1196744, rs1196768,rs3751191and rs1107756) using primer extension of multiplex products withdetection by matrix-assisted laser desorption/ionisation time-offlight massspectroscopy. We found significant evidence of association with overweight/obesityfor rs2272495and rs1107756. rs2272495C allele and rs1107756T allele bothconferred a higher risk of being overweight and obese (OR=1.218,95%CI1.047–1.416, P=0.011for rs2272495; OR=1.166,95%CI1.014–1.341, P=0.031for rs1107756). After adjusting multiple comparisons, only the effect of rs2272495onoverweight/obesity remained to be significant (empirical P=0.043). Moreover,rs2272495was associated with BMI (P=0.015), waist circumference (P=0.006), hipcircumference (P=0.025) as well as WHR (P=0.047) under a recessive model.Similar associations were found for rs1107756except for WHR. Therefore, ourfindings indicate that genetic variations in APPL2are associated with obesityespecially abdominal obesity in Chinese population with normal glucose tolerance.Additionally, we measured clinical quantitative traits related to chronic liver injure,including γ-Glutamyltransferase (GGT), alanine aminotransferase (ALT) andaspartate aminotransferase (AST) and further analyzed the associations of the sixSNPs in APPL2with these indexes. We found that rs2272495and rs10861360wereassociated with serum levels of GGT (P=0.040and0.027, respectively). Thisfounding suggests that APPL2genetic variants also associate with chronic liver injure. 2. Associations between FGF21genetic variants and abdominal obesity andNAFLD in Han Chinese population with normal glucose toleranceFGF21, a hormone that is predominantly secreted by the liver, exerts effects upon themetabolism of carbohydrates and lipids. Previous studies have demonstrated thatcirculating levels of FGF21are increased in obese human and patients with NAFLD.Elevated serum levels of FGF21are closely associated with NAFLD and chronic liverinjure. In the current study, we explored the association of FGF21genetic variantswith abdominal obesity and NAFLD in Han Chinese non-diabetic population. Werecruited344non-diabetic samples from Shanghai. Anthropometric variablesincluding height, weight, waist circumference and hip circumference were measured.Clinical quantitative indexes related to chronic liver injure, serum lipid levels andFGF21concentrations were detected. Four SNPs in FGF21were selected (rs2071699,rs838136, rs838133and rs499765) and genotyped. We found significant evidence ofassociation with NALFD for rs499765. The rs499765C allele conferred a higher riskof being NAFLD (OR=1.500,95%CI1.020–2.207, P=0.039). rs499765was alsoassociated with serum levels of FGF21(P=0.030). In addition, both rs2071699andrs838136showed association to serum levels of AST (P=0.049and0.047,respectively). The SNP rs838136also showed correlation with serum ALTconcentrations after BMI adjustment (P=0.034). Moreover, rs499765associated withabdominal obesity-related measures including waist circumference (P=0.024) andWHR (P=0.034). Therefore, our findings indicate that FGF21is closely related withthe serum levels of FGF21and NAFLD in the Chinese subjects with normal glucosetolerance.3. The association and molecular mechanism of FGF21and endoplasmicreticulum stress in the hepatic lipid metabolismEndoplasmic reticulum (ER) stress activates the adaptive unfolded protein response(UPR) and represents a critical mechanism that underlies metabolic dysfunctions.FGF21, a hormone that is predominantly secreted by the liver, exerts a broad range ofeffects upon the metabolism of carbohydrates and lipids. Although increased circulating levels of FGF21have been documented in animal models and humansubjects with obesity and NAFLD, the functional connection between obesity andNAFLD-associated metabolic ER stress and FGF21has been incompletelyunderstood. Here we report that occurrence of NAFLD was associated with increasedER stress along with simultaneous elevation of FGF21expression both indiet-induced obese mice and human patients. Intraperitoneal administration of the ERstressor tunicamycin in mice resulted in hepatic steatosis, accompanied by activationof the three canonical UPR branches and increased expression of FGF21. Furthermore,the IRE1α-XBP1pathway of the UPR could directly activate the transcriptionalexpression of Fgf21. Administration of recombinant FGF21in mice alleviatedtunicamycin-induced liver steatosis, along with reduced eIF2α-ATF4-CHOP signaling.Taken together, these results suggest that hepatic FGF21is an integral physiologicalcomponent of the cellular UPR program that exerts beneficial feedback effects uponlipid metabolism through counteracting ER stress. Thus, FGF21can be involved inthe pathogenesis of obesity and NAFLD. |
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