المؤلفون: Xiaoke Ge, Bram Slütter, Joost M. Lambooij, Enchen Zhou, Zhixiong Ying, Ceren Agirman, Marieke Heijink, Antoine Rimbert, Bruno Guigas, Johan Kuiper, Christoph Müller, Franz Bracher, Martin Giera, Sander Kooijman, Patrick C.N. Rensen, Yanan Wang, Milena Schönke

المصدر: iScience, Vol 27, Iss 6, Pp 109830- (2024)

مصطلحات موضوعية: Cardiovascular medicine, Cellular physiology, Molecular genetics, Science

الوصف: Summary: The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589004224010526Test; https://doaj.org/toc/2589-0042Test

الوصول الحر: https://doaj.org/article/d72d912914924864b6d5ff9166b6b6a7Test

المؤلفون: Enchen Zhou, Xiaoke Ge, Hiroyuki Nakashima, Rumei Li, Hendrik J P van derZande, Cong Liu, Zhuang Li, Christoph Müller, Franz Bracher, Yassene Mohammed, Jan Freark deBoer, Folkert Kuipers, Bruno Guigas, Christopher K Glass, Patrick C N Rensen, Martin Giera, Yanan Wang

المصدر: EMBO Molecular Medicine, Vol 15, Iss 8, Pp n/a-n/a (2023)

مصطلحات موضوعية: desmosterol, Kupffer cell, liver X receptor, nonalcoholic steatohepatitis, Δ24‐dehydrocholesterol reductase, Medicine (General), R5-920, Genetics, QH426-470

الوصف: Abstract Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1757-4676Test; https://doaj.org/toc/1757-4684Test

الوصول الحر: https://doaj.org/article/4c911682d99b44c88efeac537e3e77c7Test

المؤلفون: Zhixiong Ying, Robin van Eenige, Xiaoke Ge, Christy van Marwijk, Joost M. Lambooij, Bruno Guigas, Martin Giera, Jan Freark de Boer, Tamer Coskun, Hongchang Qu, Yanan Wang, Mariëtte R. Boon, Patrick C.N. Rensen, Sander Kooijman

المصدر: EBioMedicine, Vol 93, Iss , Pp 104684- (2023)

مصطلحات موضوعية: Adipose tissue, Bile acid metabolism, Hepatic steatosis, Hepatic inflammation, Glucose metabolism, Lipid metabolism, Medicine, Medicine (General), R5-920

الوصف: Summary: Background: Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development. Methods: Male APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day. Findings: GIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury. Interpretation: We interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans. Funding: This work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352396423002499Test; https://doaj.org/toc/2352-3964Test

الوصول الحر: https://doaj.org/article/d8ae3b6711e4498db0d081190af4e7ceTest

المؤلفون: Kang Cheng, Z.X. Ying, L. L. Zhang, W.P. Su, T. Wang, A.A. Wang, Chengcheng Feng, Xiaoke Ge, Lifan Zhang, Y. M. Zhou

المصدر: Poultry Science. 98:887-895

مصطلحات موضوعية: Male, Meat, education, Gene Expression, Bile Acids and Salts, 03 medical and health sciences, chemistry.chemical_compound, Animal science, Abdominal fat, medicine, Animals, Carnitine, 030304 developmental biology, 0303 health sciences, Cholesterol, 0402 animal and dairy science, Acetyl-CoA carboxylase, Broiler, Lipid metabolism, 04 agricultural and veterinary sciences, General Medicine, Factorial experiment, Metabolism, Lipid Metabolism, Animal Feed, Lipids, 040201 dairy & animal science, Diet, Liver, chemistry, Dietary Supplements, Animal Science and Zoology, Energy Metabolism, Chickens, medicine.drug

الوصف: This experiment was conducted to evaluate the effects of bile acids (BAs) on the growth performance and lipid metabolism of broilers fed with different energy level diets. 480 one-day-old Arbor Acres broilers (45.01 ± 0.26 g) were allotted to a 2 × 2 factorial design with 2 levels of energy (basal or high-energy level) and 2 levels of BAs (with or without BAs supplementation), resulting in 4 groups of 8 replicates; the experiment lasted 42 d. High-energy diets decreased the feed/gain ratio (F/G) from 1 to 21 d (P0.05), and increased the liver index and abdominal fat percentage at 42 d (P0.05). The serum total triglyceride (TG) and high-density lipoprotein cholesterol at 42 d were increased by high-energy diets (P0.05), while the hepatic lipoprotein lipase (LPL) activity at 21 and 42 d was decreased (P0.05). BAs supplementation increased the body weight at 21 d and decreased the F/G during entire period (P0.05), as well as improved the carcass quality reflected by decreased abdominal fat percentage at 42 d and increased breast muscle percentage at 21 and 42 d (P0.05). The serum TG at 21 and 42 d were decreased by BAs (P0.05), and the hepatic LPL activity at 42 d was increased (P0.05). In addition, high-energy diets increased the expression of sterol regulatory element binding transcription factor 1, acetyl-CoA carboxylase, and fatty acid synthase (P0.05), while BAs diets decreased these genes expression (P0.05). Moreover, BAs supplementation also increased the expression of carnitine palmitoyltransferase 1 (P0.05), which was increased in high-energy groups (P0.05). In conclusion, BAs supplementation could increase growth performance, elevate carcass quality, and improve lipid metabolism in broilers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5900ae00cc7e94a98aa35118704c1120Test
https://doi.org/10.3382/ps/pey434Test

المؤلفون: Yue Li, Le Zhou, Weipeng Su, Xiaoke Ge, Lili Zhang, Zhixiong Ying, Hao Zhang, Tian Wang

المصدر: Journal of Animal Science. 97:610-619

مصطلحات موضوعية: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, medicine.medical_treatment, Blood sugar, Carbohydrate metabolism, Biology, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, Internal medicine, Genetics, medicine, Weaning, reproductive and urinary physiology, 030304 developmental biology, 0303 health sciences, Methionine, Glycogen, Insulin, 0402 animal and dairy science, 04 agricultural and veterinary sciences, General Medicine, medicine.disease, 040201 dairy & animal science, female genital diseases and pregnancy complications, Endocrinology, Blood chemistry, chemistry, Animal Science and Zoology, Food Science

الوصف: This study was conducted to investigate the effects of methionine restriction (MR) on growth performance, insulin sensitivity, and hepatic and muscle glucose metabolism in intrauterine growth retardation (IUGR) pigs at 49 and 105 d of age. At weaning (day 21), 30 female normal birth weight (NBW) piglets were fed control diets with adequate methionine (NBW-CON), whereas 60 female IUGR piglets were fed either the control diets (IUGR-CON) or MR diets which were 30% reduced in methionine (IUGR-MR) (n = 6 replicates (pens) with five piglets per replicate). At 49 and 105 d of age, one pig with a BW near to the mean of each replication was selected for biochemical analysis. Compared with NBW-CON pigs, IUGR-CON pigs exhibited lower relative daily gain (RDG) and homeostasis model assessment of insulin resistance (HOMA-IR) index at day 49 (P 0.05). Compared with IUGR-CON pigs, IUGR-MR pigs had lower RDG at day 49, less blood glucose at day 105, and lower HOMA-IR index at both days 49 and 105 (P < 0.05). Additionally, compared with IUGR-CON pigs, MR decreased IUGR-MR pigs' hepatic G6Pase activities and increased their hepatic glycogen contents at day 105 (P < 0.05), as well as increased their hepatic and muscle PKB/Akt phosphorylation (P < 0.05). In conclusion, the ability of dietary MR to restrict IUGR pigs' growth and to reduce blood glucose appeared, respectively, in earlier and later period, but MR improved IUGR pigs' insulin sensitivity at both days 49 and 105.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::6f3e1f1c63fd3279e7593e67b69e7795Test
https://doi.org/10.1093/jas/sky457Test

المؤلفون: Lili Zhang, Chengcheng Feng, Xiaoke Ge, Anan Wang, Kaiwen Bai, Tian Wang, Yongwei Zhao

المصدر: Journal of Animal Science. 96:3791-3803

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, Antioxidant, medicine.medical_treatment, Weanling, Biology, Feed conversion ratio, Dimethylglycine, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Genetics, medicine, Weaning, chemistry.chemical_classification, Glutathione peroxidase, 0402 animal and dairy science, 04 agricultural and veterinary sciences, General Medicine, Malondialdehyde, 040201 dairy & animal science, 030104 developmental biology, Endocrinology, chemistry, Alkaline phosphatase, Animal Science and Zoology, Food Science

الوصف: Dimethylglycine sodium salt (DMG-Na) has exhibited excellent advantages in animal experiments and human health. The present study aimed to investigate the effects of dietary supplementation with 0.1% DMG-Na on the growth performance, hepatic antioxidant capacity, and mRNA expression of mitochondria-related genes in low birth weight (LBW) piglets during weaning period. Sixteen piglets with normal birth weight (NBW) and 16 LBW piglets were fed either a basal diet or a 0.1% DMG-Na supplemented diet from age of 21 to 49 d. Blood and liver samples were collected at the end of the study. The results showed that compared with NBW piglets, LBW piglets exhibited greater (P < 0.05) alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase activities in the serum. LBW decreased (P < 0.05) the activity of glutathione peroxidase and increased (P < 0.05) the contents of malondialdehyde and H2O2 in liver. DMG-Na supplementation increased (P < 0.05) body weight gain, feed intake, and feed efficiency, decreased (P < 0.05) ALT and AST activities, and reduced the content of H2O2 in LBW piglets. LBW piglets had downregulated (P < 0.05) mRNA expression of thioredoxin 2, thioredoxin reductases 2, and nuclear respiratory factor-1 (Nrf1) in the liver. However, DMG-Na supplementation increased (P < 0.05) mRNA expression of Nrf1 in the liver. In conclusion, DMG-Na supplementation has beneficial effects in alleviating LBW-induced hepatic oxidative damage and changed mitochondrial genes expression levels, which is associated with increased antioxidant enzyme activities and up-regulating mRNA gene abundance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4f647265218d17527245411b23673116Test
https://doi.org/10.1093/jas/sky233Test

المؤلفون: Zhixiong, Ying, Xiaoke, Ge, Hao, Zhang, Weipeng, Su, Yue, Li, Le, Zhou, Lili, Zhang, Tian, Wang

المصدر: Journal of animal science. 97(2)

مصطلحات موضوعية: Blood Glucose, Male, Swine Diseases, Fetal Growth Retardation, Litter Size, Swine, Muscles, Animal Health and Well Being, Weaning, Glucose, Methionine, Liver, Animals, Female, Insulin Resistance, Phosphorylation, Proto-Oncogene Proteins c-akt

الوصف: This study was conducted to investigate the effects of methionine restriction (MR) on growth performance, insulin sensitivity, and hepatic and muscle glucose metabolism in intrauterine growth retardation (IUGR) pigs at 49 and 105 d of age. At weaning (day 21), 30 female normal birth weight (NBW) piglets were fed control diets with adequate methionine (NBW-CON), whereas 60 female IUGR piglets were fed either the control diets (IUGR-CON) or MR diets which were 30% reduced in methionine (IUGR-MR) (n = 6 replicates (pens) with five piglets per replicate). At 49 and 105 d of age, one pig with a BW near to the mean of each replication was selected for biochemical analysis. Compared with NBW-CON pigs, IUGR-CON pigs exhibited lower relative daily gain (RDG) and homeostasis model assessment of insulin resistance (HOMA-IR) index at day 49 (P < 0.05), but higher RDG and HOMA-IR index at day 105 (P < 0.05). Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase) activities were higher in IUGR-CON than NBW-CON pigs at both days 49 and 105 (P < 0.05), while hepatic glycogen synthase and glycogen phosphorylase activities were lower in IUGR-CON pigs at both two ages (P < 0.05). In addition, compared with NBW-CON pigs, IUGR-CON pigs (105-d old) had lower protein kinase B phosphorylation (PKB/Akt) in liver (P < 0.05), but not in muscle (P > 0.05). Compared with IUGR-CON pigs, IUGR-MR pigs had lower RDG at day 49, less blood glucose at day 105, and lower HOMA-IR index at both days 49 and 105 (P < 0.05). Additionally, compared with IUGR-CON pigs, MR decreased IUGR-MR pigs’ hepatic G6Pase activities and increased their hepatic glycogen contents at day 105 (P < 0.05), as well as increased their hepatic and muscle PKB/Akt phosphorylation (P < 0.05). In conclusion, the ability of dietary MR to restrict IUGR pigs’ growth and to reduce blood glucose appeared, respectively, in earlier and later period, but MR improved IUGR pigs’ insulin sensitivity at both days 49 and 105.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::f6a5c708ec8db779d653fc8a80485166Test
https://pubmed.ncbi.nlm.nih.gov/30508105Test

المؤلفون: Shuxiang Yu, Xiaoke Geng, Huibing Liu, Yunyun Zhang, Xiumei Cao, Baojie Li, Jianshe Yan

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 9, p 8103 (2023)

مصطلحات موضوعية: ELMO1, neutrophil, chemotaxis, peritonitis, inflammation, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Peritoneal inflammation remains a major cause of treatment failure in patients with kidney failure who receive peritoneal dialysis. Peritoneal inflammation is characterized by an increase in neutrophil infiltration. However, the molecular mechanisms that control neutrophil recruitment in peritonitis are not fully understood. ELMO and DOCK proteins form complexes which function as guanine nucleotide exchange factors to activate the small GTPase Rac to regulate F-actin dynamics during chemotaxis. In the current study, we found that deletion of the Elmo1 gene causes defects in chemotaxis and the adhesion of neutrophils. ELMO1 plays a role in the fMLP-induced activation of Rac1 in parallel with the PI3K and mTORC2 signaling pathways. Importantly, we also reveal that peritoneal inflammation is alleviated in Elmo1 knockout mice in the mouse model of thioglycollate-induced peritonitis. Our results suggest that ELMO1 functions as an evolutionarily conserved regulator for the activation of Rac to control the chemotaxis of neutrophils both in vitro and in vivo. Our results suggest that the targeted inhibition of ELMO1 may pave the way for the design of novel anti-inflammatory therapies for peritonitis.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/9/8103Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/e0640acc776842009330fce3ab5f609eTest