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Fibroblast growth factor 21 (FGF21) is an endocrine hormone which signals to multiple tissues to regulate metabolism. FGF21 and another endocrine FGF, fibroblast growth factor 15/19 (FGF15/19), signal to target tissues by binding to the co-receptor ß-klotho (KLB), which then facilitates the interaction of these different FGFs with their preferred FGF receptor. KLB is expressed in multiple metabolic tissues, but the specific cell types and spatial distribution of these cells are not known. Furthermore, while circulating FGF21 is primarily produced by the liver, recent publications have indicated that brain derived FGF21 impacts memory and learning. Here, we use reporter mice to comprehensively assess KLB and FGF21 expression throughout the body. These data provide an important resource for guiding future studies to identify important peripheral and central targets of FGFs and to determine the significance of non-hepatic FGF21 production.

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Introduction: Ji-Ni-De-Xie (JNDX) is a traditional herbal preparation in China. It is widely used to treat type 2 diabetes mellitus (T2DM) in traditional Tibetan medicine system. However, its antidiabetic mechanisms have not been elucidated. The aim of this study is to elucidate the underlying mechanism of JNDX on bile acids (BAs) metabolism and FXR/FGF15 signaling pathway in T2DM rats. Methods: High-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QQQ-MS) and UPLC-Q-Exactive Orbitrap MS technology were used to identify the constituents in JNDX. High-fat diet (HFD) combined with streptozotocin (45 mg∙kg-1) (STZ) was used to establish a T2DM rat model, and the levels of fasting blood-glucose (FBG), glycosylated serum protein (GSP), homeostasis model assessment of insulin resistance (HOMA-IR), LPS, TNF-α, IL-1ß, IL-6, TG, TC, LDL-C, HDL-C, and insulin sensitivity index (ISI) were measured to evaluate the anti-diabetic activity of JNDX. In addition, metagenomic analysis was performed to detect changes in gut microbiota. The metabolic profile of BAs was analyzed by HPLC-QQQ-MS. Moreover, the protein and mRNA expressions of FXR and FGF15 in the colon and the protein expressions of FGF15 and CYP7A1 in the liver of T2DM rats were measured by western blot and RT-qPCR. Results: A total of 12 constituents were identified by HPLC-QQQ-MS in JNDX. Furthermore, 45 chemical components in serum were identified from JNDX via UPLC-Q-Exactive Orbitrap MS technology, including 22 prototype components and 23 metabolites. Using a T2DM rat model, we found that JNDX (0.083, 0.165 and 0.33 g/kg) reduced the levels of FBG, GSP, HOMA-IR, LPS, TNF-α, IL-1ß, IL-6, TG, TC, and LDL-C, and increased ISI and HDL-C levels in T2DM rats. Metagenomic results demonstrated that JNDX treatment effectively improved gut microbiota dysbiosis, including altering some bacteria (e.g., Streptococcus and Bacteroides) associated with BAs metabolism. Additionally, JNDX improved BAs disorder in T2DM rats, especially significantly increasing cholic acid (CA) levels and decreasing ursodeoxycholic acid (UDCA) levels. Moreover, the protein and mRNA expressions of FXR and FGF15 of T2DM rats were significantly increased, while the expression of CYP7A1 protein in the liver was markedly inhibited by JNDX. Discussion: JNDX can effectively improve insulin resistance, hyperglycemia, hyperlipidemia, and inflammation in T2DM rats. The mechanism is related to its regulation of BAs metabolism and activation of FXR/FGF15 signaling pathway.

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Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health issue. Changes in the gut microbiota structure and composition are closely related to host pathophysiology processes. Pectin is associated with several beneficial health effects. In the present study, we aimed at investigating the effect of tomato pectin (TP) on hepatic steatosis and exploring the underlying mechanisms by focusing on the regulation of the gut microbiota-bile acid axis. Our results showed that TP attenuated high-fat diet (HFD)-induced liver steatosis and inflammation. TP administration increased the diversity of gut microbiota, enhancing the abundance of beneficial bacteria and suppressing the abundance of harmful or conditional pathogenic bacteria. Further antibiotic-caused microbiome depletion confirmed that the anti-NAFLD activities of TP were dependent on the regulation of gut microbiota. Besides, TP intervention affected feces bile acid metabolism and caused significant changes in functional conjugated bile acids, which in turn inhibited the ileum FXR/FGF15 signaling, leading to stimulation of the hepatic bile acid (BA) production. Furthermore, TP treatment accelerated BA excretion, promoted BA transportation, inhibited BA reabsorption, and facilitated cholesterol efflux to relieve HFD-induced hyperlipidemia. These findings provide a potential dietary intervention strategy for TP against NAFLD via modulation of cross-talk between BAs and gut bacteria.

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ETHNOPHARMACOLOGICAL RELEVANCE: Tianma-Gouteng granules (TGG) is a traditional Chinese medicine (TCM) compound that was first recorded by modern medical practitioner Hu Guangci in "New Meaning of the Treatment of Miscellaneous Diseases in Traditional Chinese Medicine". It is widely used to treat hypertensive vertigo, headache and insomnia. AIM OF STUDY: To investigate the antihypertensive effect of TGG and explore its mechanism. MATERIALS AND METHODS: Spontaneously hypertensive rats (SHR) were prepared a model of the ascendant hyperactivity of liver yang syndrome (AHLYS), blood pressure and general state of rats were recorded. A series of experiments were performed by enzyme-linked immunosorbent assay (ELISA), ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), 16S rRNA sequencing, real-time fluorescence quantitative PCR (RT-qPCR), and enzymatic colorimetry. RESULTS: TGG can effectively lower blood pressure and improve related symptoms. TGG significantly reduced the levels of IL-1ß, IL-6, TNF-α, Renin and AngII. A total of 17 differential metabolites were found in plasma, with the two most potent metabolic pathways being glycerophospholipid metabolism and primary bile acid biosynthesis. After TGG intervention, 7 metabolite levels decreased and 10 metabolite levels increased. TGG significantly increased the relative abundance of Desulfovibio, Lachnoclostridium, Turicibacter, and decreased the relative abundance of Alluobaculum and Monoglobu. TGG also downregulated Farnesoid X Receptor (FXR) and Fibroblast Growth Factor 15 (FGF15) levels in the liver and ileum, upregulated Cholesterol 7α-hydroxylase (CYP7A1) levels, and regulated total bile acid (TBA) levels. CONCLUSION: TGG can regulate bile acid metabolism through liver-gut axis, interfere with related intestinal flora and plasma metabolites, decrease blood pressure, and positively influence the pathologic process of SHR with AHLYS. When translating animal microbiota findings to humans, validation studies are essential to confirm reliability and applicability, particularly through empirical human research.

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Lotus root (LR) is prone to browning after harvest due to the oxidation of phenolic compounds by polyphenol oxidase (PPO). This study compared the effects of LR extract and BLR extract on cholesterol metabolism in high-fat diet (HFD) mice. Our findings highlighted the innovative potentiality of BLR extract in effectively regulating cholesterol metabolism via inhibiting the intestinal FXR-FGF15 signaling pathway and boosting probiotics in gut microbiota, offering valuable insights for hypercholesterolemia and metabolic disorders. In detail, catechin was the main phenolic compound in LR, while after browning, theaflavin was the main oxidation product of phenolic compounds in BLR. Both the intake of LR extract and BLR extract regulated the disorder of cholesterol metabolism induced by HFD. In particular, BLR extract intake exhibited more robust effects on increasing the BAs contents synthesized in the liver and excreted in feces compared with LR extract intake. Furthermore, the consumption of BLR extract was more effective than that of LR extract in reducing the ileal protein expressions of FXR and FGF15 and shifting BAs biosynthesis from the classical pathway to the alternative pathway. Moreover, LR extract and BLR extract had distinct effects on the gut microbiota in HFD-fed mice: BLR extract significantly elevated probiotics Akkermansia abundance, while LR extract increased Lactobacillus abundance. Therefore, both LR extract and BLR extract improved the cholesterol deposition effectively and BLR extract even showed a stronger effect on regulating key gene and protein expressions of cholesterol metabolism.

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Background: Imbalances in bile acid (BA) synthesis and metabolism are involved in the onset of diabetes and depression in humans and rodents. However, the role of BAs and the farnesoid X receptor (FXR)/fibroblast growth factor (FGF) 15 signaling pathway in the development of diabetes and depression is still largely unknown. Therefore, we investigated the potential molecular mechanisms of BAs that may be associated with glucolipid metabolism disorders in diabetic mice subjected to chronic stress. Methods: The type 2 diabetes mellitus (T2DM) mouse model was induced by feeding mice a high-fat diet and administering an intraperitoneal injection of streptozotocin (STZ). The chronic unpredictable mild stress (CUMS) procedure was performed by introducing a series of mild stressors. Forty mice were randomly divided into the regular chow feeding group and the high-fat diet feeding group. After two weeks of feeding, the mice were randomly divided into four groups: the Control group, CUMS group, T2DM group, and T2DM+CUMS group. The T2DM group and T2DM+CUMS group received an intraperitoneal injection of STZ to induce the T2DM model. The CUMS and T2DM+CUMS groups were exposed to CUMS to induce depressive-like phenotypes. Blood and tissue samples were obtained for pertinent analysis and detection. Results: Compared with the T2DM mice, T2DM+CUMS mice had higher blood glucose and lipid levels, insulin resistance, inflammation of the liver and pancreas, impaired liver function, and increased total bile acids. These changes were accompanied by attenuated FXR signaling. Chronic stress was found to attenuate FXR expression and its downstream target, FGF15, in the ileum when compared with the T2DM group. Conclusion: FXR may play a role in the diabetic disorder of glucolipid metabolism when aggravated by chronic stress. FXR and its downstream target, FGF15, may be therapeutic targets for treating comorbid T2DM and depression.

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Background & Aims: The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Mdr2/Abcb4 knockout (-/-) mouse model of sclerosing cholangitis. Methods: FVB/N wild-type and Mdr2-/- or BALB/c wild-type and Mdr2-/- mice were treated with 0, 10, 30 or 90 mg/kg cilofexor by gavage every 24 h for 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline content, and picrosirius red and F4/80 immunostaining, were investigated. Bile flow, biliary bicarbonate and BA output, and hepatic BA profile, were assessed. Results: Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Mdr2-/- animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated Mdr2-/- mice. Intrahepatic BA concentrations were lowered in cilofexor-treated Mdr2-/- mice, while hepatobiliary bile flow and bicarbonate output were increased. Conclusion: Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Mdr2-/- mouse model of sclerosing cholangitis. Impact and implications: Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the Mdr2-/- mouse model. These findings indicate, that pharmacological stimulation of intestinal FXR-mediated gut-liver signaling, via fibroblast growth factor 15 (thereby reducing bile acid synthesis), may be sufficient to attenuate cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.

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Alcoholic liver disease (ALD) is a growing public health issue with high financial, social, and medical costs. Lonicera caerulea, which is rich in polyphenolic compounds, has been shown to exert anti-oxidative and anti-inflammatory effects. This study aimed to explore the effects and mechanisms of concentrated Lonicera caerulea juice (LCJ) on ALD in mice. ALD was established in mice via gradient alcohol feeding for 30 days. The mice in the experimental group were given LCJ by gavage. The reduction of aspartate transaminase (AST) and alanine transaminase (ALT) in the serum of mice indicated that LCJ has a liver-protective effect. LCJ improved the expression of AMPK, PPARα, and CPT1b in ALD mice to reduce the liver lipid content. Additionally, LCJ increased the expression of farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), and fibroblast growth factor receptor 4 (FGFR4), which lowers the expression of cytochrome P450 7A1 (CYP7A1) and lessens bile acid deposition in the liver. In mice, LCJ improved the intestinal barrier by upregulating the expression of mucins and tight junction proteins in the small intestine. Moreover, it accelerated the restoration of microbial homeostasis in both the large and small intestines and increased short-chain fatty acids in the cecum. In conclusion, LCJ alleviates ALD by reducing liver and serum lipid accumulation and modulating the FXR-FGF15 signaling pathway mediated by gut microbes.

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FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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BACKGROUND & AIMS: Glucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4-/- mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis. METHODS: Mdr2-/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and electrophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed. RESULTS: Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2-/- mice. Primary HSCs isolated from Mdr2-/- mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 (P < .05). Electrophoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgfß-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2-/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR. Serum Fgf15 levels were increased in Mdr2-/- mice treated with GLP-2. Accordingly, GLP-2 treatment of human intestinal organoids activated their FXR-FGF19 signaling axis. CONCLUSIONS: GLP-2 treatment increased NR4a1/Nur77 activation in HSCs, subsequently attenuating their activation. GLP-2 promoted intestinal Fxr-Fgf15/19 signaling resulting in reduced Cyp7a1 and increased Cyp2c70 expression in the liver, contributing to hepatoprotective and antifibrotic effects of GLP-2 in the Mdr2-/- mouse model.

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Gyejibongnyeong-hwan (GBH), a traditional Chinese medicine, is used in clinical practice to treat blood stasis in metabolic diseases. Herein, we examined the effects of GBH on dyslipidemia and investigated the underlying mechanisms by focusing on modulation of the gut microbiota-bile acid axis by GBH. We utilized a Western diet-induced dyslipidemia mouse model and divided animals into the following four groups (n = 5 each): the normal chow diet, vehicle control (WD), simvastatin (Sim, 10 mg/kg/day simvastatin; positive control), and GBH (GBH, 300 mg/kg/day) groups. The drugs were administered for 10 weeks, and morphological changes in the liver and aorta were analyzed. The mRNA expression of genes related to cholesterol metabolism, gut microbiota, and bile acid profiles were also evaluated. The GBH group showed significantly lower levels of total cholesterol, accumulation of lipids, and inflammatory markers in the liver and aorta of Western diet-fed mice. Low-density lipoprotein cholesterol levels were significantly lower in the GBH group than in the WD group (P < 0.001). The expression of cholesterol excretion-associated genes such as liver X receptor alpha and ATP-binding cassette subfamily G member 8, as well as the bile acid synthesis gene cholesterol 7 alpha-hydroxylase, which lowers cholesterol in circulation, was increased. Furthermore, GBH inhibited the intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 signaling pathway through the interactions of gut microbiota with bile acids acting as FXR ligands, which included chenodeoxycholic acid and lithocholic acid. Overall, GBH improved dyslipidemia induced by a Western diet by modulating the gut microbiota-bile acid axis.

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This work aimed to investigate the alleviative mechanism of Lactobacillus plantarum LP104 (LP104) isolated from kimchi on high-fat-diet-induced dyslipidemia by targeting the intestinal flora and bile acid (BA) metabolism. Oral administration of LP104 over 8 weeks reduced body weight gain and body fat, as well as ameliorating serum and hepatic dyslipidemia in HFD-fed C57BL/6N mice significantly. LP104 intervention also increased the ileal tauro-α/ß-muricholic acid sodium salt (T-α-MCA or T-ß-MCA) and tauroursodeoxycholic acid (TUDCA) concentrations to suppress the enterohepatic farnesoid X receptor/fibroblast growth factor 15-fibroblast growth factor receptor 4 (FXR/FGF15-FGFR4) signaling pathway, which stimulated the hepatic cholic acid (CA) and chenodeoxycholic acid (CDCA) de novo synthesis through using cholesterol. Then, LP104 treatment accelerated BA excretion with the feces and cholesterol efflux to improve HFD-caused hyperlipidemia effectively. The 16S rRNA gene high-throughput sequencing revealed that LP104 promoted intestinal flora rebalance by increasing the abundances of Bacteroides, Akkermansia, Lactobacillus, and Clostridium and decreasing the abundance of Oscillospira and Coprococcus. Meanwhile, Spearman correlation analysis demonstrated that the differential flora were closely related to BA signaling molecules including CA, CDCA, T-α-MCA, T-ß-MCA, and TUDCA after LP104 intervention. These findings provided new evidence that LP104 had the potential to be used as a naturally functional food for the prevention of dyslipidemia.

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Aflatoxin B1 (AFB1) is one of major pollutant in food and feed worldwide. The purpose of this study is to investigate the mechanism of AFB1-induced liver injury. Our results showed that AFB1 caused hepatic bile duct proliferation, oxidative stress, inflammation and liver injury in mice. AFB1 exposure induced gut microbiota dysbiosis and reduced fecal bile salt hydrolase (BSH) activity. AFB1 exposure promoted hepatic bile acid (BA) synthesis and changed intestinal BA metabolism, especially increased intestinal conjugated bile acids levels. AFB1 exposure inhibited intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) signaling. Furthermore, the mice received fecal microbiota transplantation from AFB1-treated mice induced liver injury, reduced intestinal FXR signaling and increased hepatic BA synthesis. Finally, the intestine-restricted FXR agonist treatment decreased hepatic BA synthesis, ROS level, inflammation and liver injury in AFB1-treated mice. This study suggests that modifying the gut microbiota, altering intestinal BA metabolism and/or activating intestinal FXR/FGF-15 signaling may be of value for the treatment of AFB1-induced liver disease.

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BACKGROUND: Jiang-Tang-San-Huang (JTSH) pill, a traditional Chinese medicine (TCM) prescription, has long been applied to clinically treat type 2 diabetes mellitus (T2DM), while the underlying antidiabetic mechanism remains unclarified. Currently, it is believed that the interaction between intestinal microbiota and bile acids (BAs) metabolism mediates host metabolism and promotes T2DM. PURPOSE: To elucidate the underlying mechanisms of JTSH for treating T2DM with animal models. METHODS: In this study, male SD rats received high-fat diet (HFD) and streptozotocin (STZ) injection to induce T2DM and were treated with different dosages (0.27, 0.54 and 1.08 g/kg) of JTSH pill for 4 weeks; metformin was given as a positive control. Alterations of gut microbiota and BA profiles in the distal ileum were assessed by 16S ribosomal RNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. Additionally, we conducted quantitative Real Time-PCR and western blotting to determine the mRNA and protein expression levels of intestinal farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), Takeda G-protein-coupled receptor 5 (TGR5) and glucagon-like peptide 1 (GLP-1) as well as hepatic cytochrome P450, family 7, subfamily a, poly-peptide 1 (CYP7A1) and cytochrome P450, family 8, subfamily b, poly-peptide 1 (CYP8B1), which are involved in BAs metabolism and enterohepatic circulation. RESULTS: Here, the results revealed that JTSH treatment significantly ameliorated hyperglycaemia, insulin resistance (IR), hyperlipidaemia, and pathological changes in the pancreas, liver, kidney and intestine and reduced the serum levels of pro-inflammatory cytokines in T2DM model rats. 16S rRNA sequencing and UPLC-MS/MS showed that JTSH treatment could modulate gut microbiota dysbiosis by preferentially increasing bacteria (e.g., Bacteroides, Lactobacillus, Bifidobacterium) with bile-salt hydrolase (BSH) activity, which might in turn lead to the accumulation of ileal unconjugated BAs (e.g., CDCA, DCA) and further upregulate the intestinal FXR/FGF15 and TGR5/GLP-1 signaling pathways. CONCLUSION: The study demonstrated that JTSH treatment could alleviate T2DM by modulating the interaction between gut microbiota and BAs metabolism. These findings suggest that JTSH pill may serve as a promising oral therapeutic agent for T2DM.

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Farnesoid X receptor (FXR) and Takeda G protein-coupled Receptor 5 (TGR5), the intestinal bile acid (BA) receptors, regulate the gut-derived hormones including fibroblast growth factor 15/19 (FGF15/19) and serotonin (5-hydrooxytryptamine, 5-HT). Here we show that ingestion of whey protein isolate, a milk protein, significantly decreased expression of heteromeric organic solute transporter Ostα and Ostß, which is the basolateral BA transporter in the enterocyte, and increased the expression of FXR and FGF15 in C57BL6J mouse ileum and plasma FGF15 levels. In addition, the ingestion of whey protein isolate significantly suppressed expression of hepatic cholesterol-7α hydroxylase (CYP7A1), which induces the primary BA synthesis, bile salt export pump (BSEP) and sodium-taurocholate cotransporting polypeptide (NTCP), which are the key transporters for the BA excretion and uptake in the liver, and genes involved in gluconeogenesis, and decreased the primary BAs including cholic acid, taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid in the liver compared with controls. Moreover, ingestion of whey protein isolate significantly decreased the expression of TGR5, glucagon-like peptide 1 (GLP-1), and tryptophan hydroxylase1 (Tph1) in the small intestine, leading to decreases in plasma 5-HT and insulin levels. On the other hand, ingestion of the soy protein ß-conglycinin significantly increased the expression of Ostα and Ostß, and decreased the expression of FGF15 in the ileum and plasma FGF15 levels, leading to the increases in expression of hepatic CYP7A1, BSEP, NTCP, and genes involved in gluconeogenesis, and the primary BAs in the liver. Moreover, ingestion of ß-conglycinin significantly increased the expression of intestinal TGR5, GLP-1, and Tph1, leading to increases in plasma 5-HT and insulin levels. These findings suggest that whey protein and ß-conglycinin have opposite effects on intestinal FGF15 and 5-HT secretion in mice.

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Macroautophagic/autophagic degradation of lipid droplets, lipophagy, is activated by fasting but repressed by feeding. Surprisingly, our recent study showed that this is not the case in the gut, where feeding activates lipophagy, reducing intestinal lipid levels. Transgenic mouse studies revealed that feeding activation of gut lipophagy requires both FGF15/FGF19 (fibroblast growth factor 15/fibroblast growth factor 19) and an orphan nuclear receptor, NR0B2/SHP (nuclear receptor subfamily 0, group B, member 2). Mechanistically, feeding-induced FGF15/FGF19 activates intestinal PRKC/PKC signaling, which in turn phosphorylates NR0B2 and the autophagic activator TFEB (transcription factor EB), leading to their nuclear localization and transcriptional induction of lipophagy network genes, including Ulk1 and Pnpla2/Atgl. Given that an essential function of the gut is to distribute dietary lipids throughout the body, this study identifies a physiologically important homeostatic mechanism to maintain healthy lipid levels. The intestinal FGF15/FGF19-NR0B2/SHP-TFEB pathway that regulates postprandial lipids by lipophagic activation, thus, may provide novel targets for treating dyslipidemia and obesity.

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Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/ß-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

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BACKGROUND: Insulin resistance precedes metabolic syndrome which increases the risk of type 2 diabetes and cardiovascular disease. However, there is a lack of safe and long-lasting methods for the prevention and treatment of insulin resistance. Gut microbiota dysbiosis can lead to insulin resistance and associated glucose and lipid metabolic dysfunction. Thus, the role of gut microbiota in metabolic diseases has garnered growing interest. Curcumin, the active ingredient of tropical plant Curcuma longa, has excellent prospects for the prevention and treatment of metabolic diseases. However, due to the extremely low bioavailability of curcumin, the mechanisms by which curcumin increases insulin sensitivity remains to be elucidated. This study aimed to elucidate the role of gut microbiota in mediating the effects of curcumin on improving insulin sensitivity in high-fat diet (HFD)-fed mice. METHODS: Glucose, insulin, and pyruvate tolerance were tested and hepatic triglycerides (TGs) content was measured in HFD-fed mice treated with curcumin (100 mg kg-1 d-1, p.o.) or vehicle for 4 weeks and aforementioned mice after gut microbiota depletion via antibiotic treatment for 4 weeks. Fecal microbiota transplantation (FMT) was conducted in endogenous gut microbiota-depleted HFD-fed mice. Glucose and lipid metabolic phenotypes were also measured in recipient mice colonized microbiota from vehicle- or curcumin-treated HFD-fed mice. The mechanisms underlying the effects of curcumin on increasing insulin sensitivity were testified by Western blotting, real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). RESULTS: Curcumin ameliorated HFD-induced glucose intolerance, insulin resistance, pyruvate intolerance, and hepatic TGs accumulation, while these effects were mediated by gut microbiota. Curcumin induced insulin-stimulated Akt phosphorylation levels in insulin-regulated peripheral tissues. The inhibitory effects of curcumin on the expressions of genes involved in hepatic gluconeogenesis and de novo lipogenesis were dependent on gut microbiota. Meanwhile, curcumin upregulated the expression of fibroblast growth factor 15 (FGF15) through gut microbiota. CONCLUSIONS: The effects of curcumin on promoting insulin sensitivity were dependent on gut microbiota in HFD-fed mice. Moreover, curcumin at least partly exerted its effects on increasing insulin sensitivity via FGF15 upregulation. This study provided new ideas on nutritional manipulations of gut microbiota for the treatment of metabolic diseases.

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Background: Fibroblast growth factor 15 (FGF15) through its FGF-receptor (FGFR)-4 inhibits hepatic inflammation. The current study aimed at investigating whether FGF15 could inhibit septic inflammation and its compensative regulatory T cell (Treg) responses in a mouse sepsis model of cecal ligation and puncture (CLP) and in vitro transwell co-culture. Methods: Following the sham or CLP procedure, male CLP C57BL/6 mice were intravenously injected with vehicle saline or FGF15 beginning at 2 h post the procedure every 12 h for three days. Some mice were euthanized and their serum and liver samples were collected for examination of cytokines and Tregs by enzyme-linked immunosorbent assay (ELISA), Western blot and flow cytometry. The remaining mice were monitored for their survival up to 14 days post procedure. Moreover, the purified hepatic CD4+ T cells were co-cultured in transwell plates with unmanipulated NCTC 1469 cells or the cells that had been transfected with the control or FGFR4-specific siRNA and treated with, or without, Lipopolysaccharides (LPS) for 24 h, followed by treatment with vehicle PBS or FGF15 for 48 h. Results: Compared with the CLP group of mice, treatment with FGF15 significantly prolonged the mean survival days of mice (12 vs 1.17 in the CLP group, P = 0.022), mitigated hepatic inflammation and reduced the frequency of apoptotic cells in the liver of mice. FGF15 treatment decreased the percentages of hepatic Tregs, hepatic IL-2, TGF-ß and FOXP3 expression in septic mice, accompanied by decreasing serum IL-1ß, TNF-α, IL-6 and IL-10 levels. Similarly, FGF15 treatment also attenuated the LPS-increased frequency of Tregs, FOXP3 and IL-2 expression and IL-1ß, TNF-α, IL-6 and IL-10 secretion in vitro after co-culture with NCTC 1469 cells, but not co-cultured FGFR4-silenced NCTC 1649 cells. Conclusion: FGF15 treatment through FGFR4 ameliorated hepatic inflammation and its compensative Treg responses, which were associated with protecting from septic death in mice.

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Background: Bile acids are important signaling molecules that might activate hypothalamic neurons. This study aimed to investigate possible changes in hypothalamic pro-opiomelanocortin (POMC) neurons after biliary diversion in diabetic rats. Methods: Ten GK rats were randomly divided into the biliary diversion (BD) and sham groups. The glucose metabolism, hypothalamic POMC expression, serum bile acid profiles, and ileal bile acid-specific receptors of the two groups were analyzed. Results: Biliary diversion improved blood glucose (P = 0.001) and glucose tolerance (P = 0.001). RNA-Seq of the hypothalamus showed significantly upregulated expression of the POMC gene (log2-fold change = 4.1, P < 0.001), which also showed increased expression at the protein (P = 0.030) and mRNA (P = 0.004) levels. The POMC-derived neuropeptide α-melanocyte stimulating hormone (α-MSH) was also increased in the hypothalamus (2.21 ± 0.11 ng/g, P = 0.006). In addition, increased taurocholic acid (TCA) (108.05 ± 20.62 ng/mL, P = 0.003) and taurodeoxycholic acid (TDCA) (45.58 ± 2.74 ng/mL, P < 0.001) were found in the BD group and induced the enhanced secretion of fibroblast growth factor-15 (FGF15, 74.28 ± 3.44 pg/ml, P = 0.001) by activating farnesoid X receptor (FXR) that was over-expressed in the ileum. Conclusions: Hypothalamic POMC neurons were upregulated after BD, and the increased TCA, TDCA, and the downstream gut-derived hormone FGF15 might activate POMC neurons.

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