Project description:FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2+/- mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, VilinCreert2 ; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6R611C substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.
Project description:Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.
Project description:Obesity is characterized by lipid accumulation in distinct organs. Presently, fenofibrate is a commonly used triglyceride-lowering drug. This study is designed to investigate whether long-term fenofibrate intervention can attenuate lipid accumulation in ob/ob mouse, a typical model of obesity. Our data demonstrated that fenofibrate intervention significantly decreased plasma triglyceride level by 21.0%, increased liver index and hepatic triglyceride content by 31.7 and 52.1%, respectively, and elevated adipose index by 44.6% compared to the vehicle group. As a PPARα agonist, fenofibrate intervention significantly increased the expression of PPARα protein in the liver by 46.3% and enhanced the expression of LDLR protein by 3.7-fold. However, fenofibrate dramatically increased the expression of PPARγ and SREBP-1c proteins by ~2.1- and 0.9-fold in the liver, respectively. Fenofibrate showed no effects on the expression of genes-related to fatty acid β-oxidation. Of note, it significantly increased the gene expression of FAS and SCD-1. Furthermore, fenofibrate modulated the gut microbiota. Collectively, long-term fenofibrate induces lipid accumulation in liver and adipose tissues in ob/ob mice by enhancing the expression of adipogenesis-related proteins and gut microbiota. These data suggest that fenofibrate may have limited effects on attenuating lipid deposition in obese patients.
Project description:ObjectivesArginine vasopressin (AVP), known as an antidiuretic hormone, is also crucial in metabolic homeostasis. Although AVP receptor-deficient mice exhibit various abnormalities in glucose and lipid metabolism, the mechanism underlying these symptoms remains unclear. This study aimed to explore the involvement of the gut hormones including glucagon-like peptide-1 (GLP-1) and microbiota as essential mediators.MethodsWe used the mouse GLP-1-secreting cell line, GLUTag, and performed live cell imaging to examine the contribution of V1a and V1b vasopressin receptors (V1aR and V1bR, respectively) to GLP-1 secretion. We next investigated the hormone dynamics of V1aR-deficient mice (V1aR-/- mice), V1bR-deficient mice (V1bR-/- mice), and V1aR/V1bR-double deficient mice (V1aR-/-V1bR-/-mice).ResultsAVP induced the increase in intracellular Ca2+ levels and GLP-1 secretion from GLUTag cells in a V1aR and V1bR-dependent manner. AVP receptor-deficient mice, particularly V1aR-/-V1bR-/- mice, demonstrated impaired secretion of GLP-1 and peptide YY secreted by enteroendocrine L cells. V1aR-/-V1bR-/-mice also exhibited abnormal lipid accumulation in the brown adipose tissue and skeletal muscle. We discovered that V1aR-/-V1bR-/- mice showed increased Paneth cell-related gene expression in the small intestine, which was attributed to increased fecal butyric acid levels. Exposure to butyric acid reduced GLP-1 secretion in L cell line. Additionally, human Paneth cell-related gene expressions negatively correlated with that of V1 receptor genes.ConclusionsThe deficiency in V1 receptor genes may increase gut butyric acid levels and impair the function of L cells, thus dysregulating lipid homeostasis in the brown adipose tissue and skeletal muscle. This study highlights the importance of appropriate control of the gut microbiota and its metabolites, including butyric acid, for the optimum functioning of enteroendocrine cells.
Project description:Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid-microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway.
Project description:The gut microbiota is a complex system, playing a peculiar role in regulating innate and systemic immunity. Increasing evidence links dysfunctional gut microbiota to metabolic dysfunction-associated steatotic liver disease (MASLD) due to the activation of multiple pathways in the gut and in the liver, including those mediated by Toll-like receptors (TLRs), that sustain hepatic inflammation. Thus, many efforts have been made to unravel the role of microbiota-associated dysfunction in MASLD, with the final aim of finding novel strategies to improve liver steatosis and function. Moreover, recent evidence underlines the role of adipose tissue in sustaining hepatic inflammation during MASLD development. In this review, we focus on the recently discovered strategies proposed to improve the alteration of gut microbiota observed in MASLD patients, with a particular insight into those known to modulate gut microbiota-associated dysfunction and to affect the complex crosstalk between the gut, the adipose tissue, and the liver.
Project description:The small intestine and liver play important role in determining oral drug's fate. Both organs are also interconnected through enterohepatic circulation, which imply there are crosstalk through circulating factors such as signaling molecules or metabolites that may affect drug metabolism. Coculture of hepatocytes and intestinal cells have shown to increase hepatic drug metabolism, yet its crosstalk mechanism is still unclear. In this study, we aim to elucidate such crosstalk by coculturing primary human hepatocytes harvested from chimeric mouse (PXB-cells) and iPSc-derived intestinal cells in a microphysiological systems (MPS). Perfusion and direct oxygenation from the MPS were chosen and confirmed to be suitable features that enhanced PXB-cells albumin secretion, cytochrome P450 (CYP) enzymes activity while also maintaining barrier integrity of iPSc-derived intestine cells. Results from RNA-sequencing showed significant upregulation in gene ontology terms related to fatty acids metabolism in PXB-cells. One of such fatty acids, arachidonic acid, enhanced several CYP enzyme activity in similar manner as coculture. From the current evidences, it is speculated that the release of bile acids from PXB-cells acted as stimuli for iPSc-derived intestine cells to release lipoprotein which was ultimately taken by PXB-cells and enhanced CYP activity.
Project description:iNOS deficiency in ob/ob mice improved liver inflammation and ECM remodeling-related genes, decreasing fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in hepatocytes, suggesting an important role of this alarmin in the development of NAFLD.
Project description:Background: Statin has been widely used to treat hyperlipidemia because of its high potency in decreasing cholesterol levels. The present study aimed to examine the lipid-lowering effect of rosuvastatin and the composition, diversity and species abundance of gut microbiome in association with rosuvastatin efficacy.Trial registrationChiCTR-ORC-17013212 at the First Affiliated Hospital of Dalian Medical University, November 2, 2017. Results: Totally 64 patients with hyperlipidemia were treated with 10 mg/day of rosuvastatin for 4-8 weeks. Blood lipid indicators triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL-C) were measured before and after the treatment. Stool samples were collected right after the treatment. Following total DNA extraction and PCR amplification of 16S rRNA gene, Illumina sequencing was performed for gut microbiome identification, classification and characterization. All the patients showed a significant blood lipid reduction after the treatment. The patients were grouped according to parallel manner design. Group I had 33 patients whose blood lipid levels dropped to the normal levels from week 4, with 58.5% reduction in LDL-C and 26.6% reduction in TC. Group II had 31 patients whose blood lipid levels were still above the normal levels after 8 weeks therapy, but with 41.9% reduction in LDL-C and 31.2% reduction in TC. Based on Operational Taxonomic Unit data, Alpha-diversity by Shannon Index was different between the two groups, and beta-diversity by Principle Component Analysis exhibited separated patterns of the two groups. The differences were also observed in the relative-abundance at phylum, family, and genus levels of the two groups. Linear discriminate analysis illustrated that the abundance of 29 taxa was higher in group I, while the abundance of other 13 taxa was higher in group II. Phyla Firmicutes and Fusobacteria had negative correlation to LDL-C level, but Cyanobacteria and Lentisphaerae had a positive correlation to LDL-C level. Moreover, gender and age were also found somehow correlated to microbial community composition. Conclusion: Rosuvastatin therapy had different blood lipid-lowering effect on hyperlipidemia. The gut microbiota exhibited variation in community composition, diversity and taxa in association to rosuvastatin hypolipidemic effect. These results indicate that modulation of gut microflora, especially the negative/positive correlated species might strengthen statin efficacy in statin-inadequate patients.