المؤلفون: Hans-Peter Hammes, Elena Heidenreich, Peter P. Nawroth, Martina U. Muckenthaler, Sandro Altamura, Thomas Fleming, Andrea Schlotterer, Katja Müdder, Ruiyue Qiu

المصدر: Molecular Metabolism, Vol 51, Iss, Pp 101235-(2021)
Molecular Metabolism

مصطلحات موضوعية: 0301 basic medicine, Blood Glucose, Male, DR, diabetic retinopathy, Hepcidin, medicine.disease_cause, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, MetS, Metabolic Syndrome, Internal medicine, biology, Fpn, Ferroportin, Fatty liver, Liver, DIOS, dysmetabolic iron overload syndrome, CRP, C-reactive protein, Receptors, Leptin, HH, hereditary hemochromatosis, Original Article, IRP, Iron Regulatory Protein, medicine.medical_specialty, Iron Overload, Iron, 030209 endocrinology & metabolism, Mice, Transgenic, IR, Insulin Resistance, SEM, standard error of the mean, 03 medical and health sciences, Insulin resistance, ROS, reactive oxygen species, NASH, Non Alcoholic Steatohepatitis, NAFLD, medicine, Animals, Humans, Molecular Biology, business.industry, NTBI, Non Transferrin Bound Iron, Cell Biology, medicine.disease, RC31-1245, IRS1, Db/db Mouse, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, NAFLD, Non Alcoholic Fatty Liver Disease, Lipid Peroxidation, Steatosis, Metabolic syndrome, business, Oxidative stress, IRE, Iron Responsive Element, T2DM, Type 2 Diabetes Mellitus

الوصف: Objective The molecular pathogenesis of late complications associated with type 2 diabetes mellitus (T2DM) is not yet fully understood. While high glucose levels indicated by increased HbA1c only poorly explain disease progression and late complications, a pro-inflammatory status, oxidative stress, and reactive metabolites generated by metabolic processes were postulated to be involved. Individuals with metabolic syndrome (MetS) frequently progress to T2DM, whereby 70% of patients with T2DM show non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, and insulin resistance (IR). Epidemiological studies have shown that T2DM and steatosis are associated with alterations in iron metabolism and hepatic iron accumulation. Excess free iron triggers oxidative stress and a switch towards a macrophage pro-inflammatory status. However, so far it remains unclear whether hepatic iron accumulation plays a causative role in the generation of IR and T2DM or whether it is merely a manifestation of altered hepatic metabolism. To address this open question, we generated and characterized a mouse model of T2DM with IR, steatosis, and iron overload. Methods Leprdb/db mice hallmarked by T2DM, IR and steatosis were crossed with Fpnwt/C326S mice with systemic iron overload to generate Leprdb/db/Fpnwt/C326S mice. The resulting progeny was characterized for major diabetic and iron-related parameters. Results We demonstrated that features associated with T2DM in Leprdb/db mice, such as obesity, steatosis, or IR, reduce the degree of tissue iron overload in Fpnwt/C326S mice, suggesting an ‘iron resistance’ phenotype. Conversely, we observed increased serum iron levels that strongly exceeded those in the iron-overloaded Fpnwt/C326S mice. Increased hepatic iron levels induced oxidative stress and lipid peroxidation and aggravated IR, as indicated by diminished IRS1 phosphorylation and AKT activation. Additionally, in the liver, we observed gene response patterns indicative of de novo lipogenesis and increased gluconeogenesis as well as elevated free glucose levels. Finally, we showed that iron overload in Leprdb/db/Fpnwt/C326S mice enhances microvascular complications observed in retinopathy, suggesting that iron accumulation can enhance diabetic late complications associated with the liver and the eye. Conclusion Taken together, our data show that iron causes the worsening of symptoms associated with the MetS and T2DM. These findings imply that iron depletion strategies together with anti-diabetic drugs may ameliorate IR and diabetic late complications.
Highlights • T2DM causes an iron resistance phenotype. • Iron affects hepatic insulin resistance. • Systemic iron accumulation aggravates diabetic pericyte loss.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::746ad7abfa625d87337f2502f8e59462Test
http://www.sciencedirect.com/science/article/pii/S2212877821000806Test

المؤلفون: Carrie E. McCurdy, Kenneth N. Maclean, Paul Kievit, Bryan C. Bergman, Rachel C. Janssen, Peter R. Baker, Christopher M. Mulligan, Tyler Dean, Diana L. Takahashi, Travis Nemkov, Kjersti Aagaard, Hua Jiang, Stephanie R. Wesolowski, Angelo D'Alessandro, Jacob E. Friedman

المصدر: Molecular Metabolism, Vol 18, Iss, Pp 25-41 (2018)
Molecular Metabolism

مصطلحات موضوعية: 0301 basic medicine, Steatosis, VIP, variable importance in projection, Hypoxemia, AUC, area under the curve, PC, phosphatidylcholine, 0302 clinical medicine, WSD, Western-style diet, Non-alcoholic Fatty Liver Disease, Pregnancy, Fetal programming, Hyperlipidemia, DAG, diacylglyceride, VLDL, very low-density lipoprotein, Hypoxia, 2. Zero hunger, TG, triglyceride, NEFA, non-esterified fatty acid, NHP, non-human primate, Fatty liver, 3. Good health, Liver, Lipotoxicity, CON, control, OB-WSD, Western-style diet induced obesity group, IV-GTT, intravenous glucose tolerance test, Prenatal Exposure Delayed Effects, Original Article, Female, Diet, Healthy, PLS-DA, partial least squares discriminant analysis, TCA, tricarboxylic acid cycle, NAFLD, non-alcoholic fatty liver disease, lcsh:Internal medicine, medicine.medical_specialty, Offspring, NASH, non-alcoholic steatohepatitis, Citric Acid Cycle, Metabolomic, 030209 endocrinology & metabolism, DNL, de novo lipogenesis, TBARs, thiobarbituric acid reactive substances, OB-DR, diet reversal group, 03 medical and health sciences, Fetus, Internal medicine, medicine, TBARS, Animals, Obesity, AA, amino acid, lcsh:RC31-1245, Molecular Biology, Triglycerides, business.industry, Gluconeogenesis, Maternal Nutritional Physiological Phenomena, Cell Biology, medicine.disease, Oxidative Stress, 030104 developmental biology, Endocrinology, Diet, Western, Macaca, business

الوصف: Objective Non-alcoholic fatty liver disease (NAFLD) risk begins in utero in offspring of obese mothers. A critical unmet need in this field is to understand the pathways and biomarkers underlying fetal hepatic lipotoxicity and whether maternal dietary intervention during pregnancy is an effective countermeasure. Methods We utilized a well-established non-human primate model of chronic, maternal, Western-style diet induced obesity (OB-WSD) compared with mothers on a healthy control diet (CON) or a subset of OB-WSD mothers switched to the CON diet (diet reversal; OB-DR) prior to and for the duration of the next pregnancy. Fetuses were studied in the early 3rd trimester. Results Fetuses from OB-WSD mothers had higher circulating triglycerides (TGs) and lower arterial oxygenation suggesting hypoxemia, compared with fetuses from CON and OB-DR mothers. Hepatic TG content, oxidative stress (TBARs), and de novo lipogenic genes were increased in fetuses from OB-WSD compared with CON mothers. Fetuses from OB-DR mothers had lower lipogenic gene expression and TBARs yet persistently higher TGs. Metabolomic profiling of fetal liver and serum (umbilical artery) revealed distinct separation of CON and OB-WSD groups, and an intermediate phenotype in fetuses from OB-DR mothers. Pathway analysis identified decreased tricarboxylic acid cycle intermediates, increased amino acid (AA) metabolism and byproducts, and increased gluconeogenesis, suggesting an increased reliance on AA metabolism to meet energy needs in the liver of fetuses from OB-WSD mothers. Components in collagen synthesis, including serum protein 5-hydroxylysine and hepatic lysine and proline, were positively correlated with hepatic TGs and TBARs, suggesting early signs of fibrosis in livers from the OB-WSD group. Importantly, hepatic gluconeogenic and arginine related intermediates and serum levels of lactate, pyruvate, several AAs, and nucleotide intermediates were normalized in the OB-DR group. However, hepatic levels of CDP-choline and total ceramide levels remained high in fetuses from OB-DR mothers. Conclusions Our data provide new metabolic evidence that, in addition to fetal hepatic steatosis, maternal WSD creates fetal hypoxemia and increases utilization of AAs for energy production and early activation of gluconeogenic pathways in the fetal liver. When combined with hyperlipidemia and limited antioxidant activity, the fetus suffers from hepatic oxidative stress and altered intracellular metabolism which can be improved with maternal diet intervention. Our data reinforce the concept that multiple “first hits” occur in the fetus prior to development of obesity and demonstrate new biomarkers with potential clinical implications for monitoring NAFLD risk in offspring.
Graphical abstract Image 1
Highlights • Maternal WSD increases fetal hypoxemia and utilization of AAs for gluconeogenesis. • Maternal WSD increases fetal oxidative stress and precursors to liver fibrosis. • Carnosine and l-proline uniquely correlated with fetal TG and oxidative stress. • Fetal TGs were correlated with fetal arterial oxygen saturation. • Diet reversal in obese WSD mothers prevents fetal hypoxemia and oxidative stress.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b06dccd8288a52f01636dbe7fd72ba0fTest
https://doi.org/10.1016/j.molmet.2018.09.008Test

المؤلفون: Thomas Laeger, Louise Fritsche, Christian Baumeier, Norbert Stefan, Annette Schürmann, Sophie Saussenthaler, Andreas Fritsche, Robert W. Schwenk, Maria Rödiger, Hans-Ulrich Häring, Luisa Schlüter, Stella Amelie Alaze

المصدر: Molecular Metabolism
Mol. Metab. 6, 1254-1263 (2017)
Molecular Metabolism, Vol 6, Iss 10, Pp 1254-1263 (2017)

مصطلحات موضوعية: 0301 basic medicine, Male, HFD, high-fat diet, PPARγ, medicine.medical_treatment, CD36, Adipose tissue, AST, aspartate aminotransferase, SM, skeletal muscle, Mice, F4/80, adhesion G protein-coupled receptor E1, GGT, gamma-glutamyl transpeptidase, Non-alcoholic Fatty Liver Disease, Insulin, rmDPP4, recombinant mouse dipeptidyl peptidase 4, rhDPP4, recombinant human dipeptidyl peptidase 4, Fatty liver, Ad, adenovirus, sWAT, subcutaneous white adipose tissue, Hep G2 Cells, Middle Aged, Dgat2, diacylglycerol O-acyltransferase 2, Cd36, Dpp4, Glp-1, Insulin Resistance, Nafld, Pparγ, TNFα, tumor necrosis factor α, Liver, Cpt1a, carnitine palmitoyltransferase 1a, MOGAT1, monoacylglycerol O-acyltransferase 1, Original Article, Female, medicine.symptom, PPARγ, peroxisome proliferator activated receptor gamma, Dpp4-Liv-Tg, transgenic mice with hepatocyte-specific Dpp4 overexpression, NFκB, nuclear factor-κB, Adult, lcsh:Internal medicine, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, Akt, Akt serine–threonine protein kinase, HOMA-IR, homeostatic model assessment for insulin resistance, IL6, interleukin 6, NASH, non-alcoholic steatohepatitis, Dipeptidyl Peptidase 4, gWAT, gonadal white adipose tissue, Inflammation, Srebf1, sterol regulatory element binding transcription factor 1, Mice, Transgenic, Biology, DPP4, 03 medical and health sciences, Insulin resistance, Internal medicine, NAFLD, ALT, alanine aminotransferase, medicine, Animals, Humans, ApoB, apolipoprotein B, GLP-1, glucagon-like peptide 1, Obesity, lcsh:RC31-1245, Molecular Biology, pAkt, phosphorylated Akt serine–threonine protein kinase, Cell Biology, medicine.disease, CD36, fatty acid translocase, DPP4, dipeptidyl peptidase 4, WT, wild-type, BAT, brown adipose tissue, Insulin receptor, Disease Models, Animal, 030104 developmental biology, Endocrinology, biology.protein, Hepatocytes, Gfp, green fluorescent protein, Steatosis, GLP-1, MCP1, chemokine (C-C motif) ligand 2, MAPK, mitogen-activated protein kinase

الوصف: Objective Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. Methods Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity. In vitro experiments on HepG2 cells and primary mouse hepatocytes were conducted to validate cell autonomous effects of DPP4 on lipid storage and insulin sensitivity. Results Subjects suffering from insulin resistance and NAFLD show an increased plasma DPP4 activity when compared to healthy controls. Analysis of Dpp4-Liv-Tg mice revealed elevated systemic DPP4 activity and diminished active GLP-1 levels. They furthermore show increased body weight, fat mass, adipose tissue inflammation, hepatic steatosis, liver damage and hypercholesterolemia. These effects were accompanied by increased expression of PPARγ and CD36 as well as severe insulin resistance in the liver. In agreement, treatment of HepG2 cells and primary hepatocytes with physiological concentrations of DPP4 resulted in impaired insulin sensitivity independent of lipid content. Conclusions Our results give evidence that elevated expression of DPP4 in the liver promotes NAFLD and insulin resistance. This is linked to reduced levels of active GLP-1, but also to auto- and paracrine effects of DPP4 on hepatic insulin signaling.
Graphical abstract Image 1
Highlights • NAFLD patients have augmented plasma DPP4 activity. • Hepatocyte-specific DPP4 overexpression in mice.(1)promotes fatty liver disease.(2)induces hepatic insulin resistance.(3)reduces systemic levels of active GLP-1.(4)enhances adipose tissue expansion and inflammation.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ec108ccaaae2e081b54e4ea79fe8b459Test

المؤلفون: Alexandra K. Leamy, Jamey D. Young, Robert A. Egnatchik, Masakazu Shiota, David A. Jacobson

المصدر: Molecular Metabolism

مصطلحات موضوعية: NAFLD, non-alcoholic fatty liver disease, medicine.medical_specialty, SERCA, NASH, non-alcoholic steatohepatitis, SFA, saturated fatty acid, chemistry.chemical_element, Biology, Calcium, Mitochondrion, medicine.disease_cause, PA, palmitate, Calcium in biology, PI, propidium iodide, 03 medical and health sciences, chemistry.chemical_compound, H2DCFDA, 2′,7′-dichlorodihydrofluorescein diacetate, ROS, reactive oxygen species, 0302 clinical medicine, BAPTA, Fatty liver, Internal medicine, CAC, citric acid cycle, FFA, free fatty acid, MUFA, monounsaturated fatty acid, medicine, Molecular Biology, MFA, metabolic flux analysis, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, APE, atom percent enrichment, Metabolic flux analysis, Cell Biology, SERCA, sarcoplasmic-endoplasmic reticulum calcium ATPase, 3. Good health, Endocrinology, chemistry, Lipotoxicity, Oxidative stress, OA, oleate, 030220 oncology & carcinogenesis, Original Article, BSA, bovine serum albumin, GC–MS, gas chromatography–mass spectrometry, ER stress

الوصف: Palmitate overload induces hepatic cell dysfunction characterized by enhanced apoptosis and altered citric acid cycle (CAC) metabolism; however, the mechanism of how this occurs is incompletely understood. We hypothesize that elevated doses of palmitate disrupt intracellular calcium homeostasis resulting in a net flux of calcium from the ER to mitochondria, activating aberrant oxidative metabolism. We treated primary hepatocytes and H4IIEC3 cells with palmitate and calcium chelators to identify the roles of intracellular calcium flux in lipotoxicity. We then applied (13)C metabolic flux analysis (MFA) to determine the impact of calcium in promoting palmitate-stimulated mitochondrial alterations. Co-treatment with the calcium-specific chelator BAPTA resulted in a suppression of markers for apoptosis and oxygen consumption. Additionally, (13)C MFA revealed that BAPTA co-treated cells had reduced CAC fluxes compared to cells treated with palmitate alone. Our results demonstrate that palmitate-induced lipoapoptosis is dependent on calcium-stimulated mitochondrial activation, which induces oxidative stress.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c8abb056af369ca34e6c97f53de9251Test