Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.     

Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production

Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine-brain axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine-brain-liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.     

胆汁酸及FXR在细胞增生和分化中的作用研究进展

 胆汁酸具有多种重要的生理功能,不仅与脂类物质的消化吸收密切相关,还可作为激素样信号分子在胆汁酸、脂类与糖类物质代谢及能量代谢等方面发挥重要作用。近年研究发现,胆汁酸及其核受体法尼酯X受体（FXR）在细胞增生、分化、凋亡和肝再生的调控中也发挥重要作用。本文综述了胆汁酸及其核受体FXR在细胞增生、分化、凋亡和肝再生的作用及机制,以及在寄生虫-细粒棘球绦虫成虫发育分化中作用的研究进展。     

部分水解瓜尔豆胶对高脂高糖饮食诱导小鼠代谢紊乱的调节作用

部分水解瓜尔豆胶(partially hydrolyzed guar gum,PHGG)是一种有益于代谢平衡的可溶性膳食纤维,但其对糖脂代谢紊乱的调节效果及其潜在机制尚不明确。利用高脂高糖饮食诱导小鼠16周,使其产生明显的脂代谢紊乱和胰岛素抵抗,进一步通过检测小鼠糖耐量、血清生化指标、脂肪形态、肠道短链脂肪酸及相关mRNA的表达,考察PHGG对模型小鼠的糖脂代谢稳态及肠道环境的调节作用。结果表明:长期高脂高糖饮食条件下,PHGG组小鼠比模型组小鼠的体质量增长率减缓,空腹血糖降低,葡萄糖耐量和胰岛素耐量显著提升；血清中的甘油三酯、总胆固醇、低密度脂蛋白胆固醇和游离脂肪酸可分别降低21.56%、32.67%、25.66%和22.91%,明显抑制了脂肪积累。PHGG将肠道胰高血糖素样肽-1的分泌提升并恢复到67.76pmol/L,盲肠中的丁酸含量比模型组提升了7.14倍。定量PCR显示,PHGG干预后小鼠短链脂肪酸受体GPR43的蛋白表达水平比模型组提升了63.30%。本研究表明,PHGG通过调节短链脂肪酸影响脂联素、胰岛素的分泌,进而改善高脂高糖饮食引起的糖脂代谢紊乱,可以应用于辅助糖脂代谢调控的功能性食品开发中。     

影响肝功能衰竭患者短期预后的多因素分析及其与年龄的交互作用对预后影响

为探究肝功能衰竭患者短期预后的影响因素并初步探讨年龄与相关因素交互作用对预后的影响。通过回顾南京中医药大学附属南京医院2020年6月-2022年5月收治的肝功能衰竭患者作为研究对象，采集患者入院时人口学特征、并发症、住院期间实验室检查指标，采用单因素、二元Logistic回顾分析研究影响肝衰患者预后的相关因素，采用受试者工作特征曲线（ROC）评估模型效能，采用R语言分析年龄与独立危险因素的交互作用对预后影响。结果表明：共纳入371例患者，治疗2周预后良好组257（69.27%），预后不良组114（30.73%），单因素筛选可能的影响因素有并发症数量、肝性脑病、胆汁酸最低值、胆汁酸变化率、直接胆红素最低和最高值、直接胆红素变化率、肌酐、尿素氮（P＜0.1），二元Logistic回归分析结果发现并发症数量[1.287(95%CI:1.049-1.58), P=0.016]、胆汁酸最低值[1.007(95%CI:1-1.013), P=0.007]及直接胆红素最小值[1.008(95%CI:1.001-1.014), P=0.015]、肌酐[1.008(95%CI:1.001-1.016), P=0.028]、CRP[1.012(95%CI:1-1.025), P=0.047]以及肝性脑病[4.509(95%CI:2.469-8233), P<0.001]为肝衰患者的独立影响因素（P＜0.05），ROC曲线显示并发症数量临界值2.5个，AUC 0.713(95%CI：0.656~0.771)、胆汁酸最低值临界值57.8 μmol·L-1，AUC 0.607(95%CI：0.546~0.668)、直接胆红素最低值临界值71.05 μmol·L-1，AUC 0.705 (95%CI：0.648~0.762)、肌酐临界值77.5 μmol·L-1，AUC 0.585(95%CI：0.522~0.649)、CRP临界值22.99 mg·L-1，AUC 0.550 (95%CI：0.484~0.615)，联合预测因子ROC曲线下面积AUC 0.809，敏感性：66.7%，特异性：83.7%，年龄与胆汁酸最低值、直接胆红素最低值及肝性脑病对预后影响存在协同作用。可见基于肝衰竭患者并发症数量、胆汁酸最低值、直接胆红素最低值，肌酐及肝性脑病构建的logistic回归模型具有较好的预测分类能力，具备高龄和高胆汁酸、高直接胆红素最低值、高肌酐及肝性脑病阳性因素的患者不良预后风险的概率可能更高。     

Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity

The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.     

Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice

The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(?/?), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(?/?) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.     

CREB regulates hepatic gluconeogenesis through the coactivator PGC-1

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined. Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycaemia [corrected] and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in liver contributes importantly to the pathogenesis of this disease.     

气相内标-标准曲线法测定DLPC中亚油酸

通过大豆醇溶性磷脂与亚油酸在1,3-特异脂肪酶TLIM催化下的酸解反应,制备二亚油酰磷脂酰胆碱(DLPC),衍生化处理后,气相色谱定量分析.为满足实际需求,建立了气相色谱准确定量分析DLPC中亚油酸含量的方法——内标标准曲线法.方法的相对标准偏差(RSD)2.15%,平均回收率在92.7%～105%之间,线性相关系数0.9991,线性范围在2～40mg/mL之间.     

Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells

Antagonistic activities of glucagon and insulin control metabolism in mammals, and disruption of this balance underlies diabetes pathogenesis. Insulin-producing cells (IPCs) in the brain of insects such as Drosophila also regulate serum glucose, but it remains unclear whether insulin is the sole hormonal regulator of glucose homeostasis and whether mechanisms of glucose-sensing and response in IPCs resemble those in pancreatic islets. Here we show, by targeted cell ablation, that Drosophila corpora cardiaca (CC) cells of the ring gland are also essential for larval glucose homeostasis. Unlike IPCs, CC cells express Drosophila cognates of sulphonylurea receptor (Sur) and potassium channel (Ir), proteins that comprise ATP-sensitive potassium channels regulating hormone secretion by islets and other mammalian glucose-sensing cells. They also produce adipokinetic hormone, a polypeptide with glucagon-like functions. Glucose regulation by CC cells is impaired by exposure to sulphonylureas, drugs that target the Sur subunit. Furthermore, ubiquitous expression of an akh transgene reverses the effect of CC ablation on serum glucose. Thus, Drosophila CC cells are crucial regulators of glucose homeostasis and they use glucose-sensing and response mechanisms similar to islet cells.     

Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors.

Peroxisomes are cytoplasmic organelles which are important in mammals in modulation of lipid homeostasis, including the metabolism of long-chain fatty acids and conversion of cholesterol to bile salts (reviewed in refs 1 and 2). Amphipathic carboxylates such as clofibric acid have been used in man as hypolipidaemic agents and in rodents they stimulate the proliferation of peroxisomes. These agents, termed peroxisome proliferators, and all-trans retinoic acid activate genes involved in peroxisomal-mediated beta-oxidation of fatty acids. Here we show that the receptor activated by peroxisome proliferators and the retinoid X receptor-alpha (ref. 6) form a heterodimer that activates acyl-CoA oxidase gene expression in response to either clofibric acid or the retinoid X receptor-alpha ligand, 9-cis retinoic acid, an all-trans retinoic acid metabolite; simultaneous exposure to both activators results in a synergistic induction of gene expression. These data demonstrate the coupling of the peroxisome proliferator and retinoid signalling pathways and provide evidence for a physiological role for 9-cis retinoic acid in modulating lipid metabolism.     

高脂饮食对法尼醇受体(FXR)敲除小鼠糖脂代谢及肝脏脂肪变性的影响研究

目的探讨高脂饮食对法尼醇受体（farnesoid X receptor,FXR）敲除小鼠糖脂代谢及肝脏脂肪变性的影响。方法正常饮食（normal diet,ND）组:C57BL/6（wild type,WT）小鼠（n=6）和FXR -/- 小鼠（n=6）给予辐照灭菌维持饲料喂养12周。高脂饮食（high fat diet,HFD）组:C57BL/6小鼠（n=6）和FXR -/- 小鼠（n=6）给予45%高脂饲料喂养12周。小鼠处死后全自动生化分析仪检测血清总胆固醇（total cholesterol,TC）、甘油三酯（triglyceride,TG）、低密度脂蛋白胆固醇（low density lipoprotein cholesterol,LDL-C）、高密度脂蛋白胆固醇（High density lipoprotein cholesterol,HDL-C）、谷丙转氨酶（alanine aminotransferase,ALT）、谷草转氨酶（aspartate aminotransferase,AST）和总胆汁酸（total bile acid,TBA）指标; RT-PCR检测肝脏炎症因子TNF-α、TLR4和FXR下游基因小分子异源二聚体（small heterodimer partner,SHP）、胆固醇7α-羟化酶（cholesterol 7α-hydroxylase,CYP7A1）的相对表达量; HE染色观察肝脏脂肪变性情况。结果高脂饮食喂养条件下,C57BL/6小鼠和FXR -/- 小鼠体质量变化无差异,但相比C57BL/6小鼠,FXR -/- 小鼠表现出更为严重糖耐量受损（P <0. 01）、脂质代谢紊乱（P <0. 01）、血清胆汁酸增高（P <0. 01）、肝脏炎症（P <0. 01）和肝脏脂肪变性。结论 FXR的缺失引起小鼠糖脂代谢紊乱、胆汁酸代谢异常、肝脏脂肪变性,但这种改变需要高脂饮食的诱导。     

MicroRNAs 103 and 107 regulate insulin sensitivity

Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity.