The role of FGF21 in the pathogenesis of cardiovascular disease.

ABSTRACT: The morbidity and mortality of cardiovascular diseases (CVDs) are increasing worldwide and seriously threaten human life and health. Fibroblast growth factor 21 (FGF21), a metabolic regulator, regulates glucose and lipid metabolism and may exert beneficial effects on the cardiovascular system. In recent years, FGF21 has been found to act directly on the cardiovascular system and may be used as an early biomarker of CVDs. The present review highlights the recent progress in understanding the relationship between FGF21 and CVDs including coronary heart disease, myocardial ischemia, cardiomyopathy, and heart failure and also explores the related mechanism of the cardioprotective effect of FGF21. FGF21 plays an important role in the prediction, treatment, and improvement of prognosis in CVDs. This cardioprotective effect of FGF21 may be achieved by preventing endothelial dysfunction and lipid accumulating, inhibiting cardiomyocyte apoptosis and regulating the associated oxidative stress, inflammation and autophagy. In conclusion, FGF21 is a promising target for the treatment of CVDs, however, its clinical application requires further clarification of the precise role of FGF21 in CVDs.

A Novel Antidiabetic Monomers Combination Alleviates Insulin Resistance Through Bacteria-Cometabolism-Inflammation Responses.

The present study sought to examine the therapeutic effect of a novel antidiabetic monomer combination (AMC) in treating type 2 diabetes mellitus (T2DM); while also elucidating the potential functional mechanism. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to establish T2DM. The AMC group showed significant reduction in weight, fasting blood glucose (FBG), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), and experienced reduced insulin resistance based on oral glucose tolerance testing (OGTT) and hyperinsulinemic-euglycemic clamp testing ("gold standard" for determining in vivo insulin sensitivity). Further, AMC restored the altered intestinal flora by increasing the abundance of the beneficial bacteria Akkermansia, and decreasing the number of harmful bacteria, including Bacteroides, Odoribacter, Prevotella 9, Alistipes, and Parabacteroides. Components of the host-microbial metabolome were also significantly changed in the AMC group compared to the HFD group, including hydroxyphenyllactic acid, palmitoleic acid, dodecanoic acid, linoleic acid, and erucic acid. Furthermore, AMC was found to inhibit inflammation and suppress signaling pathways related to insulin resistance. Lastly, spearman correlation analysis revealed relationships between altered microbial community and co-metabolite levels, co-metabolites and inflammatory cytokines. Hence, the potential mechanism responsible for AMC-mediated alleviation of insulin resistance was suggested to be involved in modulation of bacteria-cometabolism-inflammation responses.

Serum biomarkers combined with ultrasonography for early diagnosis of non-alcoholic fatty liver disease confirmed by magnetic resonance spectroscopy.

Magnetic resonance spectroscopy (MRS) is notably accurate for even minimal degree of hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). But routine use of MRS is limited by its cost and availability. In this study, we developed a diagnostic model combining ultrasonography with biomarkers to identify mild NAFLD, with MRS as the reference standard. A total of 422 eligible subjects were enrolled. The serum levels of fibroblast growth factor 21 (FGF21), cytokeratin 18 M65ED, proteinase 3, neutrophil elastase, alpha-1 antitrypsin, and neutrophil elastase/alpha-1 antitrypsin were measured using ELISA assays. We found that among the six biomarkers, only serum FGF21 was independently associated with intrahepatic triglyceride content (IHTC, standardized ß = 0.185, P < 0.001) and was an independent risk factor for mild NAFLD. Thus, we established a Mild NAFLD Model based on FGF21, alanine transaminase, triglycerides, and body mass index. The area under the receiver-operating characteristic curve of the Mild NAFLD Model was 0.853 (95% confidence interval: 0.816-0.886). Furthermore, a two-step approach combining ultrasonography with the Mild NAFLD Model displayed a better sensitivity for diagnosing mild NAFLD compared with each method alone, with a sensitivity of 97.32% and a negative predictive value of 85.48%. This two-step approach combining ultrasonography and the Mild NAFLD Model derived from serum FGF21 improves the diagnosis of mild NAFLD and can be applied to the early diagnosis of NAFLD in clinical practice.

Circulating miR-29b positively correlates with non-alcoholic fatty liver disease in a Chinese population.

OBJECTIVE: Early screening of non-alcoholic fatty liver disease (NAFLD) is of great significance for the early detection and intervention in NAFLD. MicroRNAs (miRNAs) are important regulators of metabolic diseases including NAFLD. The aim of this study was to investigate the association of serum miR-29a-c with NAFLD in a Chinese population. METHODS: Participants were divided into four groups based on the presence or absence of NAFLD and/or type 2 diabetes mellitus (T2DM). Quantitative polymerase chain reaction analysis was performed to quantify serum level of miR-29a-c. The association of miR-29a-c with NAFLD was evaluated. RESULTS: Serum miR-29b, but not miR-29a or miR-29c, was positively associated with NAFLD (odds ratio [OR] 2.04 [1.16- 3.58], P = 0.013). Additionally, age, serum triglyceride and fasting plasma glucose (FPG) levels were independently associated with miR-29b (ß ± standard error [SE] = 0.004 ± 0.002, P = 0.019 for age; ß ± SE = 0.110 ± 0.054, P = 0.042 for triglyceride; and ß ± SE = 0.389 ± 0.161, P = 0.016 for FPG). MiR-29b level was positively correlated with intrahepatic lipid content (ß ± SE = 6.055 ± 2.630, P = 0.024) after adjusted for age, sex, and body mass index. CONCLUSIONS: Serum miR-29b was associated with intrahepatic lipid content and NAFLD in a Chinese population-based study.

Effect of Dietary Resistant Starch on Prevention and Treatment of Obesity-related Diseases and Its Possible Mechanisms.

Overweight or obesity has become a serious public health problem in the world, scientists are concentrating their efforts on exploring novel ways to treat obesity. Nowadays, the availabilities of bariatric surgery and pharmacotherapy have enhanced obesity treatment, but it should has support from diet, physical exercise and lifestyle modification, especially the functional food. Resistant starch, an indigestible starch, has been studied for years for its beneficial effects on regulating blood glucose level and lipid metabolism. The aim of this review is to summarize the effect of resistant starch on weight loss and the possible mechanisms. According to numerous previous studies it could be concluded that resistant starch can reduce fat accumulation, enhance insulin sensitivity, regulate blood glucose level and lipid metabolism. Recent investigations have focused on the possible associations between resistant starch and incretins as well as gut microbiota. Resistant starch seems to be a promising dietary fiber for the prevention or treatment of obesity and its related diseases.

Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis.

Endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR) and represents a critical mechanism that underlies metabolic dysfunctions. Fibroblast growth factor 21 (FGF21), a hormone that is predominantly secreted by the liver, exerts a broad range of effects upon the metabolism of carbohydrates and lipids. Although increased circulating levels of FGF21 have been documented in animal models and human subjects with obesity and nonalcoholic fatty liver disease, the functional interconnections between metabolic ER stress and FGF21 are incompletely understood. Here, we report that increased ER stress along with the simultaneous elevation of FGF21 expression were associated with the occurrence of nonalcoholic fatty liver disease both in diet-induced obese mice and human patients. Intraperitoneal administration of the ER stressor tunicamycin in mice resulted in hepatic steatosis, accompanied by activation of the three canonical UPR branches and increased the expression of FGF21. Furthermore, the IRE1α-XBP1 pathway of the UPR could directly activate the transcriptional expression of Fgf21. Administration of recombinant FGF21 in mice alleviated tunicamycin-induced liver steatosis, in parallel with reduced eIF2α-ATF4-CHOP signaling. Taken together, these results suggest that FGF21 is an integral physiological component of the cellular UPR program, which exerts beneficial feedback effects upon lipid metabolism through counteracting ER stress.

[Prognosis and treatment of sudden sensorineural hearing loss with total and severe all frequency hearing loss].

OBJECTIVE: To evaluate the treatment and prognosis of sudden sensorineural hearing loss (SSHL) with total and severe all frequency hearing loss. METHODS: Sixty-two patients diagnosed as SSHL (0.25, 0.5, 1, 2, 4 kHz pure tone average > or = 56 dB) were studied from January 2003 to October 2006, in which 18 of them were treated with Xueshuantong (Panax notoginseng saponins) while 19 of them treated with steroid and Xueshuantong, and 25 of them treated with steroid, DF-521 and Xueshuantong. RESULTS: The hearing improvement rate of the patients treated with Xueshuantong was 22.2% (4/18) while the patients treated with steroid and Xueshuantong was 57.9% (11/19) and the patients treated with steroid, DF-521 and Xueshuantong was 68.0% (17/25). The good improvement rate of the patients treated with Xueshuantong was 5.6% (1/18) while the patients treated with steroid and Xueshuantong was 36.8% (7/19) and the patients treated with steroid, DF-521 and Xueshuantong was 60.0% (15/25). Over hearing improvement was significantly better in patients treated with steroid, defibrinogenation and Xueshuantong than in those treated with Xueshuantong only (P < 0.05). The patients of total hearing loss had a significantly higher vertigo rate and worse therapy effect. CONCLUSIONS: The combined therapy include high-dose corticosteroids and defibrinogenation therapy is effective for the patients with total deafness and severe all frequency hearing loss. The prognosis of patients with total hearing loss was poor.