A maple syrup extract alters lipid metabolism in obese type 2 diabetic model mice [liver]
Ontology highlight
ABSTRACT: Some polyphenols are known to improve the symptoms of diabetes. In the present study, we investigated the effects of a polyphenol-rich extract of maple syrup (MSx) on a diabetic mouse model. KK-Ay mice were fed a normal or 0.05% MSx-supplemented diet for 42 days. Body weight, food intake, serum biochemical parameters, and fecal total bile acid were measured. Gene expression of liver and epididymal white adipose tissue (WAT) and cecal microbiota were analyzed. Data were analyzed with an unpaired two-tailed Student’s t test or Welch’s t test according to the results of the F test. Serum low-density lipoprotein cholesterol levels were significantly reduced in mice that consumed MSx. Hepatic genes related to fatty acid degradation and cholesterol catabolism were upregulated in mice that consumed MSx. In contrast, the expression of genes related to lipid metabolism in WAT was unaffected by the intake of MSx. There were no significant differences between the two groups in terms of total bile acid level in the feces and the relative abundance of bacteria in the cecum. Our results primarily indicate that MSx can help alleviate one of the symptoms of dyslipidemia.
Project description:Some polyphenols are known to improve the symptoms of diabetes. In the present study, we investigated the effects of a polyphenol-rich extract of maple syrup (MSx) on a diabetic mouse model. KK-Ay mice were fed a normal or 0.05% MSx-supplemented diet for 42 days. Body weight, food intake, serum biochemical parameters, and fecal total bile acid were measured. Gene expression of liver and epididymal white adipose tissue (WAT) and cecal microbiota were analyzed. Data were analyzed with an unpaired two-tailed Student’s t test or Welch’s t test according to the results of the F test. Serum low-density lipoprotein cholesterol levels were significantly reduced in mice that consumed MSx. Hepatic genes related to fatty acid degradation and cholesterol catabolism were upregulated in mice that consumed MSx. In contrast, the expression of genes related to lipid metabolism in WAT was unaffected by the intake of MSx. There were no significant differences between the two groups in terms of total bile acid level in the feces and the relative abundance of bacteria in the cecum. Our results primarily indicate that MSx can help alleviate one of the symptoms of dyslipidemia.
Project description:Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate limiting enzyme of bile acid biosynthetic pathway to convert cholesterol to bile acids, which is a major output pathway for cholesterol catabolism. In this study, we aimed to assess the potential regulatory mechanisms of microRNA-185 (miR-185) involved in cholesterol and bile acid homeostasis. This study provides convincing evidences about the critical role of miR-185 in FoxO1 modulation at both posttranscriptional and posttranslational levels, which account for the effects on CYP7A1 gene and its mediated cholesterol-bile acid metabolism. These results suggest an important role of miR-185 as a novel atherosclerosis-protective target for drug discovery.
Project description:Nudix hydrolase 7 (NUDT7) is a peroxisomal (acyl-)CoA-degrading enzyme that is highly expressed in the liver. We previously showed that liver-specific NUDT7 overexpression affects peroxisomal lipid metabolism, but does not prevent the increase in total liver CoA levels that occurs with fasting. Herein, we show that deletion of Nudt7 alters the composition of the hepatic acyl-CoA pool in mice fed a low fat diet, but only in males fed a western diet does the lack of NUDT7 increase total liver CoA levels. This effect is driven by the accumulation of medium-chain dicarboxylic acyl-CoAs, which are products of the oxidation of dicarboxylic fatty acids in the peroxisomes. We also show that, under conditions of increased cholesterol intake and elevated bile acid synthesis, Nudt7 deletion increases the production of tauro-muricholic acids, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion. Collectively, our findings reveal a key role for NUDT7 in the regulation of the final products of bile acid synthesis and dicarboxylic fatty acid oxidation
Project description:Deoxycholic acid (DCA) is a secondary bile acid produced by a small number of commensal species of bacteria present in the mammalian gut. Elevated DCA concentration correlates with disease states including colon cancer and cholesterol gallstones, but the associated mechanisms are not fully understood. Both primary and secondary bile acids are also capable of affecting gene expression through nuclear receptors such as FXR. To better understand the impact of a commensal-derived secondary bile acid on host metabolism we fed DCA to germ-free (GF) mice, which normally lack DCA, and compared the hepatic transcriptomes of bile acid fed GF mice to GF mice receiving a control diet, as well as to those of conventionally housed control animals. Interestingly, the feeding of DCA to GF mice, but not the feeding of cholic acid (CA) from which DCA is derived, results in an up-regulation of genes of cholesterol biosynthetic pathways. GF mice normally have elevated hepatic cholesterol compared to conventionally housed mice. Despite increase in the expression of cholesterol biosynthetic genes, the DCA fed GF mice showed a markedly decreased level of hepatic cholesterol equivalent to the hepatic cholesterol concentration of conventionally colonized animals. Total cholesterol in the serum was unaffected by DCA, but there was a decrease in the HDL lipoprotein fraction as well as an increase in the non-HDL lipoprotein fraction of the serum cholesterol. DCA, but not CA, is sufficient to modulate host lipoprotein metabolism. Taken together, these results suggests that a minor component of the gut microbiome has a significant impact on cholesterol homeostasis through secondary metabolism of bile acids and suggests a possible therapeutic intervention route through the microbial metabolic pathways. two mouse strains, three diets, one time point
Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease. Eight week old Mig-6f/f vs Mig-6d/d male mice after undergoing a 24 hour fast
Project description:The study evaluated effects of dietary cholesterol (1.5%) in Atlantic salmon fed a plant based diet for 77 days. Cholesterol supplementation did not affect growth or organ weights of Atlantic salmon, but promoted induction of cholesterol and plant sterol efflux in the intestine, whereas sterol uptake was suppressed. Microarray analyses in the liver indicated decreased cholesterol biosynthesis and enhanced conversion to bile acids. The marked effect of cholesterol on bile acid synthesis suggests that dietary cholesterol can be used to stimulate bile acid synthesis in fish. The study clearly demonstrated how Atlantic salmon adjusted metabolic functions in response to the dietary load of cholesterol, and has expanded our understanding of sterol metabolism and turnover that adds to the knowledge of these processes in fish. Atlantic salmon received feeds based on plant ingredients with (CH) and without (K) supplementation of cholesterol. Liver samples were collected after 77 days. Five individuals from each group were analyzed with microarrays, pooled liver sample of salmon fed with commerical fish meal based feed was used as a reference.
Project description:Bile acid diarrhoea is a chronic condition caused by increased delivery of bile acids to the colon. The underlying mechanisms remain to be elucidated. To investigate genes involved in bile acid diarrhoea, systems-level analyses were employed on a rat bile acid diarrhoea model. Twelve male Wistar Munich rats, housed in metabolic cages, were fed either control or bile acid-mixed (1% w/w) diets for ten days. Food intake, water intake, urine volume, bodyweight and faecal output were monitored daily. After euthanasia, colonic epithelial cells were isolated using calcium-chelation and processed for systems-level analyses, i.e. RNA-sequencing transcriptomics and mass spectrometry proteomics. Bile acid-fed rats suffered diarrhoea, indicated by increased drinking, faeces weight and faecal water content compared with control rats. Urine output was unchanged. With bile acid-feeding, RNA-sequencing revealed 204 increased and 401 decreased mRNAs; mass spectrometry 183 increased and 111 decreased proteins. Among the altered genes were genes associated with electrolyte and water transport (including Slc12a7, Clca4 and Aqp3) and genes associated with bile acid transport (Slc2b1, Abcg2, Slc51a, Slc51b and Fabps). Correlation analysis showed a significant positive correlation (Pearson’s r=0.28) between changes in mRNA-expression and changes in protein-expression. However, caution must be exercised in making a direct correlation between experimentally determined transcriptomes and proteomes. Genes associated with bile acid transport responded to bile acid-feeding, suggesting that colonic bile acid transport occur by regulated protein facilitated mechanisms rather than passive diffusion. In addition, the study provides annotated rat colonic epithelial cell transcriptome and proteome with response to bile acid-feeding.
Project description:Deoxycholic acid (DCA) is a secondary bile acid produced by a small number of commensal species of bacteria present in the mammalian gut. Elevated DCA concentration correlates with disease states including colon cancer and cholesterol gallstones, but the associated mechanisms are not fully understood. Both primary and secondary bile acids are also capable of affecting gene expression through nuclear receptors such as FXR. To better understand the impact of a commensal-derived secondary bile acid on host metabolism we fed DCA to germ-free (GF) mice, which normally lack DCA, and compared the hepatic transcriptomes of bile acid fed GF mice to GF mice receiving a control diet, as well as to those of conventionally housed control animals. Interestingly, the feeding of DCA to GF mice, but not the feeding of cholic acid (CA) from which DCA is derived, results in an up-regulation of genes of cholesterol biosynthetic pathways. GF mice normally have elevated hepatic cholesterol compared to conventionally housed mice. Despite increase in the expression of cholesterol biosynthetic genes, the DCA fed GF mice showed a markedly decreased level of hepatic cholesterol equivalent to the hepatic cholesterol concentration of conventionally colonized animals. Total cholesterol in the serum was unaffected by DCA, but there was a decrease in the HDL lipoprotein fraction as well as an increase in the non-HDL lipoprotein fraction of the serum cholesterol. DCA, but not CA, is sufficient to modulate host lipoprotein metabolism. Taken together, these results suggests that a minor component of the gut microbiome has a significant impact on cholesterol homeostasis through secondary metabolism of bile acids and suggests a possible therapeutic intervention route through the microbial metabolic pathways.
Project description:Bile acids play multiple roles in vertebrate metabolism by facilitating lipid absorption in the intestine and acting as a signaling molecule in lipid and carbohydrate metabolism. Bile acids are also the main route to excrete excess cholesterol out of the body. Alpha-methyl-Coa racemase (Amacr) is one of the enzymes needed to produce bile acids from cholesterol. The mouse model lacking Amacr can produce only minor (less than 10%) amounts of bile acids, but still they are symptomless in normal laboratory conditions. Bile acid synthesis occurs in liver. In this experiment, liver samples from Amacr-/- and wild-type mice were collected and their gene expression levels were compared. 4 biological replicates per genotype.
Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.