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Erin K Zinkhan, Baifeng Yu, Amnon Schlegel
Intrauterine growth restriction (IUGR) and consumption of a high saturated fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. The mechanism through which the cumulative impact of IUGR and in utero exposure to a maternal HFD increase cholesterol levels remains unknown. Cholesterol 7α hydroxylase (Cyp7a1) initiates catabolism of cholesterol to bile acids for elimination from the body, and is regulated by microRNA-122 (miR-122). We hypothesized that IUGR rats exposed to a maternal HFD would have increased cholesterol and decreased Cyp7a1 protein levels in juvenile rats, findings which would be normalized by administration of a miR-122 inhibitor...
2018: Frontiers in Physiology
Fan Ying, Yin Cai, Hoi Kin Wong, Xin Yi Chen, Ianto Bosheng Huang, Paul M Vanhoutte, Zhengyuan Xia, Aimin Xu, Eva Hoi Ching Tang
Prostaglandin E receptor subtype 4 (EP4) knockout mice develops spontaneous hypercholesterolemia but the detailed mechanisms by which EP4 affects cholesterol homeostasis remains unexplored. We sought to determine the cause of hypercholesterolemia in EP4 knockout mice, focusing on the role of EP4 in regulating the synthesis and elimination of cholesterol. Deficiency of EP4 significantly decreased total bile acid levels in the liver by 26.2% and the fecal bile acid content by 27.6% as compared to wild type littermates, indicating that the absence of EP4 decreased hepatic bile acid synthesis and their subsequent excretion in stools...
June 8, 2018: Biochimica et Biophysica Acta
Faten A Al-Aqil, Maria J Monte, Ana Peleteiro-Vigil, Oscar Briz, Ruben Rosales, Raquel Gonzalez, Carlos J Aranda, Borja Ocon, Iker Uriarte, Fermin Sanchez de Medina, Olga Martinez-Augustin, Matias A Avila, Jose J G Marin, Marta R Romero
At high doses, glucocorticoids (GC) have been associated with enhanced serum bile acids and liver injury. We have evaluated the effect of GC, in the absence of hepatotoxicity, on FXR/Fgf15/Fgf21-mediated ileum-liver crosstalk. Rats and mice (wild type and Fxr-/- , Fgf15-/- and int-Gr-/- strains; the latter with GC receptor (Gr) knockout selective for intestinal epithelial cells), were treated (i.p.) with dexamethasone, prednisolone or budesonide. In both species, high doses of GC caused hepatotoxicity. At a non-hepatotoxic dose, GC induced ileal Fgf15 down-regulation and liver Fgf21 up-regulation, without affecting Fxr expression...
June 5, 2018: Biochimica et Biophysica Acta
Yuji Tanaka, Takanori Ikeda, Kazuo Yamamoto, Shiori Masuda, Hiroshi Ogawa, Toshinori Kamisako
Maternal high-fat diet (HFD) consumption during pregnancy and lactation affects metabolic outcomes and lipid metabolism of offspring in later life in a gender-specific manner. However, it is not known whether maternal HFD alters bile acid metabolism in adult mice offspring. The purpose of this study was to elucidate the relationship between maternal HFDinduced metabolic diseases and bile acid metabolism in male and female adult mice offspring. Female mice were fed either standard chow (C) or HFD (H) for 10 weeks pre-pregnancy until lactation...
June 2018: Journal of Biosciences
Anna Cieślak, Jocelyn Trottier, Mélanie Verreault, Piotr Milkiewicz, Marie-Claude Vohl, Olivier Barbier
Cholestasis is characterized by the accumulation of toxic bile acids (BAs) in liver cells. The present study aimed to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, on BA homeostasis and toxicity in human cell models. The effects of EPA and/or DHA on the expression of genes involved in the maintenance of BA homeostasis were analyzed in human hepatoma (HepG2) and colon carcinoma (Caco-2) cells, as well as in primary culture of human intestinal (InEpC) and renal (RPTEC) cells...
2018: Canadian Journal of Gastroenterology & Hepatology
Prasant Kumar Jena, Lili Sheng, Nidhi Nagar, Chao Wu, Daniela Barile, David A Mills, Yui-Jui Yvonne Wan
Milk oligosaccharides (MO) selectively increase the growth of Bifidobacterium infantis (B. infantis). This study examines the effects of bovine MO and B. infantis in preventing nonalcoholic steatohepatitis (NASH) in Western diet (WD)-fed bile acid (BA) receptor FXR (farnesoid x receptor) knockout (KO) mice. WD-fed FXR KO mice have cancer-prone NASH and reduced B. infantis. MO and/or B. infantis supplementation improved their insulin sensitivity and reduced hepatic inflammation. Additionally, B. infantis, but not MO, decreased hepatic triglyceride and cholesterol...
April 25, 2018: Journal of Nutritional Biochemistry
Zhong-Xia Lu, Wen-Jun Xu, Yang-Sheng Wu, Chang-Yu Li, Yi-Tao Chen
The aim of the present study was to identify key antidiabetic nodes in the livers of pioglitazone-treated type 2 diabetes mellitus Sprague-Dawley rats by transcriptomic and proteomic analysis. Rats were randomly divided into the control, the diabetes model, and the pioglitazone-treated groups. After treatment with pioglitazone for 11 weeks, the effects on fasting blood glucose, body weight, and blood biochemistry parameters were evaluated. Microarray and iTRAQ analysis were used to determine the differentially expressed genes/proteins in rat livers...
2018: Journal of Diabetes Research
Aldo Grefhorst, Johanna C van den Beukel, Wieneke Dijk, Jacobie Steenbergen, Gardi J Voortman, Selmar Leeuwenburgh, Theo J Visser, Sander Kersten, Edith Ch Friesema, Axel Pn Themmen, Jenny A Visser
Cold exposure of mice is a common method to stimulate brown adipose tissue (BAT) activity and induce browning of white adipose tissue (WAT) that has beneficial effects on whole body lipid metabolism, including reduced plasma triglyceride (TG) concentrations. The liver is a key regulatory organ in lipid metabolism as it can take up as well as oxidize fatty acids. The liver can also synthesize, store and secrete triglycerides (TGs) in very low density lipoprotein (VLDL) particles. The effects of cold exposure on murine hepatic lipid metabolism have not been addressed...
May 9, 2018: Journal of Endocrinology
Gitte Ravn-Haren, Britta N Krath, Jarosław Markowski, Morten Poulsen, Max Hansen, Krzysztof Kołodziejczyk, Monika Kosmala, Lars O Dragsted
The mechanism behind the cholesterol lowering effects of apple pomace, a polyphenol- and fibre rich by-product in apple juice production, was investigated. Groups of male F344 rats were fed a control feed or the same feed with 2.1% or 6.5% dry apple pomace with or without seeds for 4 weeks. Effects on plasma cholesterol concentrations, excretion of bile acids, expression of genes involved in cholesterol- and bile acid synthesis, and other markers related to gut health were investigated. We found that pomace feeding decreased total-, LDL- and IDL-cholesterol concentrations compared to control...
May 9, 2018: Food & Function
Xiaoguang Gao, Changyuan Wang, Chenqing Ning, Kexin Liu, Xinyuan Wang, Zhihao Liu, Huijun Sun, Xiaodong Ma, Pengyuan Sun, Qiang Meng
Hepatic fibrosis is a pathological process that eventually leads to the development of cirrhosis and liver cancer by various types of chronic liver disease. To date, there is no standard treatment for the progression of liver fibrosis. This study aims to investigate the hepatoprotection of auraptene (AUR), a simple coumarin contained in the peels of citrus fruits such as grapefruit, against thioacetamide (TAA)-induced hepatic fibrosis in mice. The involvement of farnesoid X receptor (FXR) in the anti-fibrotic effect of AUR was further elucidated using in vivo and in vitro experiments...
May 3, 2018: Food & Function
Ruijie Gong, Xiaofei Lv, Fengqiong Liu
Background: The miRNA cluster miR-17-92 is known to act as an oncogene in various cancers. Members of this cluster were also found to be involved in some other pathological process, such as steatosis, which is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether miR-17, one of the most functional miRNAs in the miR-17-92 family, participates in the process of steatosis in hepatoma cells. Methods: We developed both a miR-17-expressing transgenic mouse model and a miR-17-expressing HepG2 cell model, the latter was established via stable transfection...
2018: Cellular & Molecular Biology Letters
Kun Tang, Fei Wang, Yi Zeng, XueMeng Chen, XiaoLe Xu
Salusin-α is an endogenous bioactive peptide and likely to prevent atherosclerosis. But its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to determine the potential effects of salusin-α on atherosclerosis and its associated metabolic disorders in high fat diet (HFD)-fed low density lipoprotein receptor deficient (LDLr-/- ) mice, and also explore the possible underlying mechanisms involved. Our data showed that after 12 weeks treatment, salusin-α ameliorated HFD-induced weight gain, hyperlipidemia, and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)...
April 25, 2018: European Journal of Pharmacology
Wenting Shang, Xu Si, Zhongkai Zhou, Padraig Strappe, Chris Blanchard
In this study, the level of gamma-aminobutyric acid (GABA) in wheat bran was increased to be six times higher through the action of endogenous glutamate decarboxylase compared with untreated bran. The process of GABA formation in wheat bran also led to an increased level of phenolic compounds with enhanced antioxidant capacity 2 times higher than the untreated status. The interventional effect of a diet containing GABA-enriched bran on hyperinsulinemia induced by a high-fat diet (HFD) was investigated in a rat model...
May 23, 2018: Food & Function
Cheng-Yuan Lin, Ling Zhao, Tao Huang, Lin Lu, Mahjabin Khan, Jie Liu, Linda L D Zhong, Zong-Wei Cai, Bao-Min Fan, Anderson O L Wong, Zhao-Xiang Bian
Spexin is a novel hormone involved in obesity and diabetes while its biofunctional significance in lipid metabolism is still to be comprehended. Global metabolomic analysis in the present study revealed multiple metabolic pathways altered by spexin intraperitoneal ( i.p .) injection in rat serum, which are highlighted by the changes in several bile acid metabolites. In rats, spexin (300 μg/kg) could dramatically reduce hepatic and circulating total bile acids (TBA) level compared with the controls. Correspondingly, treatment with spexin by i...
2018: Frontiers in Physiology
Li-Han Chen, Yi-Wen Chien, Mei-Ling Chang, Chia-Chung Hou, Ching-Hung Chan, Hung-Wei Tang, Hui-Yu Huang
Taiwanese green propolis ethanol extract (TGPE) is produced only in Taiwan and has a different composition from other types of propolis. TGPE is known for its anti-inflammation, anti-oxidation, and anti-microbial properties, but the effects and mechanisms of TGPE in the modulation of diabetes are unclear. In this study, we investigated the effects of TGPE on type 2 diabetes mellitus (T2DM) in a streptozotocin/high-fat-diet (STZ/HFD)-induced T2DM rat model. The results revealed that TGPE delayed the development and progression of T2DM and reduced the severity of β-cell failure...
April 18, 2018: Nutrients
Xiaoguang Gao, Ting Fu, Changyuan Wang, Chenqing Ning, Kexin Liu, Zhihao Liu, Huijun Sun, Xiaodong Ma, Xiaokui Huo, Xiaobo Yang, Ming Zou, Qiang Meng
Cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a newly therapeutic strategy against cholestasis. The purpose of the current study is to screen novel FXR agonists and verify the anti-cholestasis effect of yangonin in vivo and in vitro. The computational strategy of two-dimensional virtual screening was used to search for new FXR agonists, and dual-luciferase reporter gene assay was used to further demonstrate FXR activation by yangonin...
June 1, 2018: Toxicology and Applied Pharmacology
Ennian Leng, Yuan Xiao, Zhentao Mo, Yiqi Li, Yueyue Zhang, Xiaosi Deng, Min Zhou, Chaochao Zhou, Zengxuan He, Jingyi He, Lu Xiao, Junming Li, Wenna Li
BACKGROUND: Crocin (CRO), chlorogenic acid (CGA), geniposide (GEN), and quercetin (QUE) are all natural compounds with anti-obesity properties, in particular, hypolipidemic effects, which have been widely used for the treatment of obesity-related metabolic diseases. However, it is not yet known whether these compounds interact synergistically. Here, we investigated the effects and molecular mechanisms of CRO, CGA, GEN, QUE, and a combination of all four compounds (CCGQ), on lipid accumulation in human hepatoma (HepG2 cells)...
April 5, 2018: BMC Complementary and Alternative Medicine
Michelle M Chen, Clarence Hale, Shanaka Stanislaus, Jing Xu, Murielle M Véniant
Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid homeostasis in vivo ; its most closely related subfamily member, FGF19, is known to be a critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a functional role in bile acid metabolism, we evaluated the effects of short- and long-term exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models...
May 2018: Journal of Endocrinology
Sora Enya, Koichi Kawakami, Yutaka Suzuki, Shinpei Kawaoka
The nature of host organs and genes that underlie tumor-induced physiological disruption on the host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is suitable for addressing this issue, and find that hepatic cyp7a1 , the rate-limiting factor for synthesizing bile acids [or, in the case of zebrafish, bile alcohol (BA)], is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in the formation of an intestinal tumor. The local intestinal tumor caused systemic detrimental effects on the host, including liver inflammation, hepatomegaly, growth defects and organismal death...
May 3, 2018: Disease Models & Mechanisms
Faiza Qayyum, Bo K Lauridsen, Ruth Frikke-Schmidt, Klaus F Kofoed, Børge G Nordestgaard, Anne Tybjærg-Hansen
Aims: Myocardial infarction (MI) and gallstone disease (GSD) are intrinsically linked via cholesterol metabolism. We tested the hypothesis that genetic variants in the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, are associated with risk of MI and GSD in the general population. Methods and results: We performed tests of association between lipid levels and eight rare non-synonymous mutations and two common variants, rs2081687 and rs3808607, in CYP7A1 in 100 149 individuals from the general population...
February 23, 2018: European Heart Journal
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