Hormone-like fibroblast growth factors and metabolic regulation

The family of fibroblast growth factors (FGFs) consisting now of 22 members is generally considered to control a wide range of biological functions such as development, differentiation and survival. However, research during the past decade provided substantial evidence that a so called “hormone-like” subgroup of FGFs, comprised of FGF19, FGF21 and FGF23, is involved in the regulation of diverse metabolic pathways to control glucose, lipid, bile acid, phosphate and vitamin D metabolism. The unique properties of these FGFs include predominant production of the factors in selective tissues, their abundance in the blood due to the lack of extracellular heparin-mediated sequestration, and highly specific tissue-targeted action via engagement of their respective co-receptors. The important metabolic context of FGF19, FGF21, and FGF23 actions has revealed important novel roles for FGFs and provided significant means to explore an opportunity for therapeutic targeting of these factors and their corresponding pathways.     

β-Klotho在物质能量代谢及肿瘤发展中的作用

β-Klotho(KLB)是Klotho蛋白家族中一员,主要分布在肝、脂肪、胰腺、大脑等器官和组织。KLB是一种单次跨膜蛋白质,也是成纤维细胞生长因子19/21(FGF19/21)靶向激活成纤维细胞生长因子受体(FGFRs)的关键的高亲和力共受体。KLB在FGF21/19-KLB-FGFRs通路中参与机体对血糖、脂质、体重、胆汁酸循环等物质能量的调节,参与多种组织器官中细胞增殖的调节。本文将对KLB的结构特征和分布,以及在FGF19/21-KLB-FGFRs通路中对物质能量的调节作用和肿瘤形成中的作用进行综述。     

PM2.5通过抑制FGF21/AMPKα2通路促发非酒精性脂肪肝

目的:探讨PM2.5对非酒精性脂肪肝(NAFLD)的影响及与FGF21/AMPKα2通路的关系。方法:根据气管滴注的PM2.5浓度随机将40只6周龄雄性小鼠分为4组:对照组(生理盐水,10只)和低毒组(6.25μg/mL)、中毒组(12.5μg/mL)、高毒组(25.0μg/mL),10只/组,持续染毒19天。10周龄起给予高脂饲料喂养6周,构建NAFLD小鼠模型。分别于染毒前、染毒后、高脂喂养6周测定循环TG、TC及FGF21水平。处死小鼠,取肝细胞培养后随机分两组,分别转染Ad-FGF21与对照病毒Ad-GFP 16 h,后加入PM2.5混悬液进行染毒共培养36 h,测定两组细胞存活率,肝细胞内TC及TG、FGF21、AMPKα2含量。结果:染毒后及高脂喂养6周后,各组血清TG、TC较染毒前明显升高,血清FGF21水平降低,且随着染毒浓度的增加,血清TG、TC亦相应升高,FGF21随之降低(P0.05)。与染毒后比较,高脂喂养6周后各组血清TG、TC均显著升高,血清FGF21显著降低(P0.05)。与Ad-GFP组比较,Ad-FGF21组PM2.5染毒后肝细胞存活率显著升高,TG、TC水平明显降低,而肝细胞FGF21、AMPKα2表达含量则显著升高(P0.05)。结论:幼年期PM2.5暴露可加速成年后NAFLD发生,且与暴露浓度密切相关,PM2.5可能通过抑制肝脏FGF21/AMPKα2信号通路促进肝细胞脂质沉积和NAFLD的发生发展。     

血清GDF-15、FGF21与非酒精性脂肪性肝病患者肝纤维化和代谢综合征的关系研究

摘要 目的：研究血清生长分化因子15（GDF-15）、成纤维细胞生长因子21（FGF21）与非酒精性脂肪性肝病（NAFLD）患者肝纤维化和代谢综合征（MS）的关系。方法：选取我院2019年1月～2021年2月收治的102例NAFLD患者记作研究组。另选取同期健康体检志愿者100例作为对照组。比较两组血清GDF-15、FGF21与肝纤维化指标水平,并采用Pearson相关性分析明确血清GDF-15、FGF21与肝纤维化指标水平的关系。此外,将研究组患者按照是否并发MS分为MS组以及非MS组,比较MS组以及非MS组血清GDF-15、FGF21水平以及基线资料。采用多因素Logistic回归分析NAFLD并发MS的影响因素。结果：研究组血清GDF-15、FGF21水平高于对照组（均P＜0.05）。研究组血清透明质酸（HA）、层粘连蛋白（LN）、Ⅲ型前胶原（PCⅢ）以及Ⅳ型胶原（ⅣC）水平高于对照组（均P＜0.05）。经Pearson相关性分析发现,血清GDF-15、FGF21水平与血清HA、LN、PCⅢ、ⅣC水平均呈正相关关系（均P＜0.05）。经单因素分析发现,血清天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、GDF-15、FGF21水平以及体质量指数、空腹血糖（FPG）、餐后2小时血糖（2hPG）、收缩压（SBP）、舒张压（DBP）、甘油三酯（TG）均和MS有关（均P＜0.05）。经多因素Logistic回归分析发现,血清AST、ALT升高是NAFLD并发MS的保护因素,而体质量指数、GDF-15、FGF21、FPG、2hPG、SBP、DBP、TG升高均是NAFLD并发MS的危险因素（均P＜0.05）。结论：血清GDF-15、FGF21与NAFLD患者肝纤维化以及MS均密切相关,可作为预测NAFLD患者肝纤维化以及MS的辅助性生物学指标。     

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

The role of fibroblast growth factor receptor 4 (FGFR4) in regulating bile acid synthesis has been well defined; however, its reported role on glucose and energy metabolism remains unresolved. Here, we show that FGFR4 deficiency in mice leads to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat conditions. Mechanism of action studies in FGFR4-deficient mice suggest that the effects are mediated in part by increased plasma levels of adiponectin and the endocrine FGF factors FGF21 and FGF15, the latter of which increase in response to an elevated bile acid pool. Direct actions of increased bile acids on bile acid receptors, and other potential indirect mechanisms, may also contribute to the observed metabolic changes. The results described herein suggest that FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.     

基于成纤维细胞生长因子1的药物治疗肥胖相关并发症

目前,超重和肥胖的发生率已在全球范围内达到流行病的程度,这对慢性代谢性疾病预防和控制造成了巨大挑战。肥胖是包括2型糖尿病、非酒精性脂肪性肝病、心血管病、神经退行性疾病、睡眠呼吸暂停和某些类型的癌症等在内的一系列代谢疾病的主要危险因素。然而,治疗肥胖及其相关并发症的药物选择仍然有限,大多数抗肥胖药物因严重不良反应而退出市场,迫切需要开发有效的长期治疗方法来应对肥胖相关并发症。成纤维细胞生长因子1（fibroblast growth factor 1,FGF1）是全身能量稳态、糖脂代谢和胰岛素敏感性的重要调节因子。FGF1对于肥胖及2型糖尿病、非酒精性脂肪性肝病、癌症、心脏病等肥胖相关并发症具有一定的治疗益处,但长期使用导致的肿瘤发生风险增加限制了其应用。本综述总结了基于FGF1治疗肥胖相关并发症的生物药物开发的最新进展,强调了临床实施中的主要挑战,并讨论了克服这些障碍的可能策略。     

Lipase-catalyzed synthesis of phenolic lipids from fish liver oil and dihydrocaffeic acid

The enzymatic synthesis of phenolic lipids by lipase-catalyzed transesterification of dihydrocaffeic acid (DHCA) with fish liver oil was investigated in a selected organic solvent medium. These synthesized phenolic lipids have potential use as nutraceutical products. Using a molar ratio of 1:8 DHCA to fish liver oil in hexane:2-butanone mixtures of 75:25 and 85:15 (v/v), the lipase-catalyzed reaction resulted in maximum conversion of 55.8 and 65.4%, respectively. The maximum conversion of phenolic monoacylglycerols in hexane:2-butanone mixture of 75:25 and 85:15 (v/v) was 40.3 and 37.7%, respectively; using the same solvent mixtures, the conversions of the phenolic diacylglycerol were 15.8 and 36.8%, respectively. Hexane:2-butanone mixture of 75:25 (v/v) was, therefore, the best organic solvent mixture for the production of phenolic monoacylglycerols, while that of 85:15 (v/v) was best for the production of phenolic diacylglycerols. The phenolic lipids produced from the fish liver oil and DHCA demonstrated antioxidant property as indicated by its free radical scavenging capacity.     

Lipase-catalyzed synthesis of phenolic lipids from fish liver oil and dihydrocaffeic acid

The enzymatic synthesis of phenolic lipids by lipase-catalyzed transesterification of dihydrocaffeic acid (DHCA) with fish liver oil was investigated in a selected organic solvent medium. These synthesized phenolic lipids have potential use as nutraceutical products. Using a molar ratio of 1:8 DHCA to fish liver oil in hexane:2-butanone mixtures of 75:25 and 85:15 (v/v), the lipase-catalyzed reaction resulted in maximum conversion of 55.8 and 65.4%, respectively. The maximum conversion of phenolic monoacylglycerols in hexane:2-butanone mixture of 75:25 and 85:15 (v/v) was 40.3 and 37.7%, respectively; using the same solvent mixtures, the conversions of the phenolic diacylglycerol were 15.8 and 36.8%, respectively. Hexane:2-butanone mixture of 75:25 (v/v) was, therefore, the best organic solvent mixture for the production of phenolic monoacylglycerols, while that of 85:15 (v/v) was best for the production of phenolic diacylglycerols. The phenolic lipids produced from the fish liver oil and DHCA demonstrated antioxidant property as indicated by its free radical scavenging capacity.     

深海鱼油治疗阿尔茨海默病大鼠的作用及对其肠道菌群的影响

目的研究深海鱼油对阿尔茨海默病(AD)大鼠的治疗作用及其对大鼠肠道菌群的影响。方法从60只SD大鼠中随机选择50只建模并随机分为5组,其余为假手术组。石杉碱甲组灌胃石杉碱甲注射液20μg/kg,深海鱼油高、中、低剂量组分别灌胃0.21 g/kg、0.42 g/kg、0.84 g/kg深海鱼油,假手术组和模型组大鼠灌胃等体积生理盐水,大鼠给药体积按照1 mL/kg。结果第2、3、4、5 d大鼠逃避潜伏期,Aβ40、Aβ42含量,拟杆菌门、瘤胃菌科、拟杆菌科、普雷沃氏菌科、拟杆菌属、螺杆菌属、普雷沃氏菌属、链球菌属水平,模型组高于假手术组(P<0.05),石杉碱甲组和深海鱼油高、中、低剂量组均低于模型组(P<0.05);大鼠跨越平台次数,厚壁菌门、变形菌门、乳杆菌科、毛螺菌科、韦荣球菌科、乳杆菌属、瘤胃球菌属、毛螺菌属、肠球菌属、韦荣球菌属水平,模型组低于假手术组(P<0.05),石杉碱甲组和深海鱼油高、中、低剂量组均高于模型组(P<0.05)。模型组神经组织显著改变,石杉碱甲组和深海鱼油高、中、低剂量组均出现好转。结论深海鱼油可改善AD模型大鼠学习能力和记忆能力、减轻大鼠海马组织病变,改善大鼠肠道菌群。     

The broadening spectrum of mitochondrial disease: Shifts in the diagnostic paradigm

Background

The diagnosis of mitochondrial disease requires a complex synthesis of clinical, biochemical, histological, and genetic investigations. An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function. Improved understanding of the investigational pitfalls and the development of new laboratory methodologies that lead to a molecular diagnosis have necessitated the field to rapidly adopt changes to its diagnostic approach.

Scope of review

We review the clinical, investigational and genetic challenges that have resulted in shifts to the way we define and diagnose mitochondrial disease. Incorporation of changes, including the use of fibroblast growth factor 21 (FGF-21) and next generation sequencing techniques, may allow affected patients access to earlier molecular diagnosis and management.

Major conclusions

There have been important shifts in the diagnostic paradigm for mitochondrial disease. Diagnosis of mitochondrial disease is no longer reliant on muscle biopsy alone, but should include clinical assessment accompanied by the use of serological biomarkers and genetic analysis. Because affected patients will be defined on a molecular basis, oligosymptomatic mutation carriers should be included in the spectrum of mitochondrial disease. Use of new techniques such as the measurement of serum FGF-21 levels and next-generation-sequencing protocols should simplify the diagnosis of mitochondrial disease.

General significance

Improvements in the diagnostic pathway for mitochondrial disease will result in earlier, cheaper and more accurate methods to identify patients with mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

食用保健精制鱼油的开发

海鱼中富含对心血管病、癌症等中老年疾病有特殊疗效的成分——EPA、DHA等高级不饱和脂肪酸,对提取浓缩精制的原料选择,目前国外是采用优质鱼料提取的鱼油,我国多属鱼肝油系列;而占鱼产量70％以上的工业鱼粉鱼油则未利用。为了开发鱼粉鱼油的综合利用,根据我国鱼油主要来自鱼粉鱼油的实情,本文主要论证用湿法鱼粉鱼油开发研制食用保健精制鱼油的可行性。     

Long-term fermented soybean paste improves metabolic parameters associated with non-alcoholic fatty liver disease and insulin resistance in high-fat diet-induced obese mice

Recently, Korean traditional fermented soybean paste, called Doenjang, has attracted attention for its protective effect against diet-related chronic diseases such as obesity and type 2 diabetes. Long-term fermented soybean pastes (LFSPs) are made by fermentation with naturally-occurring microorganisms for several months, whereas short-term fermented soybean pastes (SFSPs) are produced by shorter-time fermentation inoculated with a starter culture. Here, we demonstrate that administration of LFSP, but not SFSP, protects high-fat diet (HFD)-fed obese mice against non-alcohol fatty liver disease (NAFLD) and insulin resistance. LFSP suppressed body weight gain in parallel with reduction in fat accumulation in mesenteric adipose tissue (MAT) and the liver via modulation of MAT lipolysis and hepatic lipid uptake. LFSP-treated mice also had improved glucose tolerance and increased adiponectin levels concomitantly with enhanced AMPK activation in skeletal muscle and suppressed expression of pro-inflammatory cytokines in skeletal muscle and the liver. LFSP also attenuated HFD-induced gut permeability and lowered serum lipopolysaccharide level, providing an evidence for its probiotic effects, which was supported by the observation that treatment of a probiotic mixture of LFSP-originated Bacillus strains protected mice against HFD-induced adiposity and glucose intolerance. Our findings suggest that the intake of LFSP, but not SFSP, offers protection against NAFLD and insulin resistance, which is an effect of long-term fermentation resulting in elevated contents of active ingredients (especially flavonoids) and higher diversity and richness of Bacillus probiotic strains compared to SFSP.