scholarly journals Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2516
Author(s):  
Ahmed Ghallab ◽  
Maiju Myllys ◽  
Adrian Friebel ◽  
Julia Duda ◽  
Karolina Edlund ◽  
...  
Keyword(s):  
Human Disease ◽  
Therapeutic Targets ◽  
Hepatocellular Cancer ◽  
Standard Diet ◽  
Ductular Reaction ◽  
Time Resolved ◽  
Ammonia Metabolism ◽  
Alcoholic Fatty Liver ◽  
Functional Changes ◽  
Sequence Of Events

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.

Towards Better Drug Repositioning: Targeted Immunoinflammatory Therapy for Diabetic Nephropathy

2019 ◽  
Vol 26 ◽  
Author(s):  
Qin zhang ◽  
Ming Yang ◽  
Ying Xiao ◽  
Yachun Han ◽  
Shikun Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Inflammatory Process ◽  
Drug Repositioning ◽  
Microvascular Complications ◽  
Pathogenic Factor ◽  
Progressive Decline ◽  
Functional Changes ◽  
Sequence Of Events ◽  
Novel Treatment

: Diabetic nephropathy (DN) is one of the most common and important microvascular complications of diabetes mellitus (DM). The main clinical features of DN are proteinuria and a progressive decline in renal function , which are associated with structural and functional changes in the kidney. The pathogenesis of DN is multifactorial, including genetic, metabolic and haemodynamic factors, which can trigger a sequence of events. Controlling metabolic risks such as hyperglycaemia, hypertension and dyslipidaemia is not enough to slow the progression of DN. Recent studies have emphasized immunoinflammation as a critical pathogenic factor in the progression of DN. Therefore, targeting inflammation is considered a potential and novel treatment strategy for DN. In this review, we will briefly introduce the inflammatory process of DN and discuss the anti-inflammatory effects of antidiabetic drugs when treating DN.

Influence of irisin on diet-induced metabolic syndrome in experimental rat model

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Dalia Medhat ◽  
Mona A. El-Bana ◽  
Sherien M. El-Daly ◽  
Magdi N. Ashour ◽  
Tahany R. Elias ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Profile ◽  
Histopathological Examination ◽  
Retinol Binding Protein ◽  
Albino Rats ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Kidney Functions

Abstract Objective To evaluate the influence of irisin on the experimental paradigm of non-alcoholic fatty liver (NAFL) as a part of MetS cluster. Methods Forty male albino rats were divided into four groups; normal control, standard diet + irisin, high carbohydrate and fat diet (HCHF), and HCHF + irisin. After the experimental period, levels of fasting blood sugar (FBS), insulin, lipid profile, kidney functions, salusin-alpha (Sal-α), adropin, and retinol-binding protein-4 (RBP-4) were evaluated. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression in skeletal muscle was evaluated by quantitative real-time PCR. Aorta, liver, pancreas, and skeletal muscle tissue samples were prepared for histopathological examination. Results Rats administrated HCHF showed elevated levels of FBS, lipid profile, kidney functions, RBP-4, and downregulation of PGC-1α expression along with a decline in levels of insulin, Sal-α, and adropin while administration of irisin significantly attenuated these levels. Conclusions Irisin as based therapy could emerge as a new line of treatment against MetS and its related diseases.

scholarly journals The Combination of Berberine, Tocotrienols and Coffee Extracts Improves Metabolic Profile and Liver Steatosis by the Modulation of Gut Microbiota and Hepatic miR-122 and miR-34a Expression in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1281
Author(s):  
Valentina Cossiga ◽  
Vincenzo Lembo ◽  
Cecilia Nigro ◽  
Paola Mirra ◽  
Claudia Miele ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Plant Extracts ◽  
Elaeis Guineensis ◽  
Low Density Lipoprotein ◽  
Liver Steatosis ◽  
Density Lipoprotein ◽  
Coffea Canephora ◽  
Standard Diet ◽  
Microbial Composition ◽  
Alcoholic Fatty Liver

Non-alcoholic-fatty liver disease (NAFLD) is spreading worldwide. Specific drugs for NAFLD are not yet available, even if some plant extracts show beneficial properties. We evaluated the effects of a combination, composed by Berberis Aristata, Elaeis Guineensis and Coffea Canephora, on the development of obesity, hepatic steatosis, insulin-resistance and on the modulation of hepatic microRNAs (miRNA) levels and microbiota composition in a mouse model of liver damage. C57BL/6 mice were fed with standard diet (SD, n = 8), high fat diet (HFD, n = 8) or HFD plus plant extracts (HFD+E, n = 8) for 24 weeks. Liver expression of miR-122 and miR-34a was evaluated by quantitativePCR. Microbiome analysis was performed on cecal content by 16S rRNA sequencing. HFD+E-mice showed lower body weight (p < 0.01), amelioration of insulin-sensitivity (p = 0.021), total cholesterol (p = 0.014), low-density-lipoprotein-cholesterol (p < 0.001), alanine-aminotransferase (p = 0.038) and hepatic steatosis compared to HFD-mice. While a decrease of hepatic miR-122 and increase of miR-34a were observed in HFD-mice compared to SD-mice, both these miRNAs had similar levels to SD-mice in HFD+E-mice. Moreover, a different microbial composition was found between SD- and HFD-mice, with a partial rescue of dysbiosis in HFD+E-mice. This combination of plant extracts had a beneficial effect on HFD-induced NAFLD by the modulation of miR-122, miR-34a and gut microbiome.

scholarly journals HEPATOPROTECTIVE EFFECT OF BANANA PEEL FLOUR ON HISTOLOGICAL AND LIVER FUNCTION IN DIABETIC RATS

2021 ◽  
pp. 529-538
Author(s):  
Herlin Ajeng Nurrahma ◽  
Andreanyta Meliala ◽  
Paramita Narwidina ◽  
Sri Herwiyanti
Keyword(s):  
Liver Function ◽  
Diabetic Rats ◽  
Hepatoprotective Effect ◽  
Banana Peel ◽  
Control Group ◽  
Standard Diet ◽  
Hepatic Enzyme ◽  
Alcoholic Fatty Liver ◽  
Group I ◽  
Male Wistar Rats

In diabetes mellitus, non-alcoholic fatty liver disease (NAFLD) is closely linked to hyperglycemia metabolism. This study aimed to find out how a banana peel supplemented diet affected histological and liver function changes in streptozotocin-induced diabetic rats. Vitamins, minerals, dietary fiber, antioxidants, and tryptophan are all contained in banana peel flour (BPF). Serotonin is a neurotransmitter that has been linked to depression and anxiety. This post-test-only control group study was conducted on twenty-five male Wistar rats which were separated into five groups with different treatments. Groups II to V were diabetic rats model groups that consumed standard diet mixed with BPF 0%, 5%, 10%, and 20%, respectively, while group I was a healthy control group fed a standard diet. Hepatic enzyme transaminase (Alanine Aminotransferase-ALT and Aspartate Aminotransferase - AST) and Hematoxylin-Eosin (HE) staining were analyzed with the NAFLD score to examine the liver function and hepatocellular morphology. A change in liver function was observed, as well as a substantial change in the levels of ALT and AST. The NAFLD score with HE staining showed substantial improvements in liver morphology, which was better seen at a 20% BPF dose. The current study supported the hypothesis that BPF had a hepatoprotective effect in diabetic rats, which may be due to the mechanism of controlling the hepatic enzyme transaminase and inducing liver regeneration.

scholarly journals Lupine (Lupinus angustifolius L.) Peptide Prevents Non-Alcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice

2019 ◽  
Author(s):  
Ana Lemus-Conejo ◽  
Elena Grao-Cruces ◽  
Rocio Toscano ◽  
Lourdes M Varela ◽  
Carmen Claro ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Lupinus Angustifolius ◽  
Standard Diet ◽  
Obese Mice ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Bioactive peptides are related to the prevention and treatment of many diseases. GPETAFLR is an octapeptide which was isolated from lupine (Lupinus angustifolius L.) and showed anti-inflammatory properties. The aim of this study was to evaluate the potential activity of GPETAFLR to prevent non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a standard diet or an HFD. Two of the groups fed the HFD diet were treated with GPETAFLR in their drinking water at 0,5 mg/kg/d or 1 mg/kg/d. To determine the ability of GPETAFLR to improve the onset and progression of NAFLD, histological studies, hepatic enzyme profile, inflammatory cytokine and lipid metabolism-related genes and proteins were analyzed. Our results suggest that HFD-induced inflammatory metabolic disorders were alleviated by treatment with GPETAFLR. In conclusion, dietary lupine consumption could repair HFD-induced hepatic damage, possibly via modifications in the liver&rsquo;s lipid signalling pathways.

Abstract 156: Involvement of β-adrenergic System in Myocardial Dysfunction Induced by Obesity

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ana Paula Lima-Leopoldo ◽  
Artur Ferron ◽  
Bruno Jacobsen ◽  
Dijon Campos ◽  
Renata Luvizotto ◽  
...  
Keyword(s):  
Myocardial Dysfunction ◽  
Myocardial Contraction ◽  
Experimental Models ◽  
The Body ◽  
Adrenergic System ◽  
Standard Diet ◽  
Adrenergic Stimulation ◽  
High Fat ◽  
Functional Changes ◽  
Adiposity Index

Several structural and functional changes of the heart have often been associated with human and experimental models of obesity. Some factors have been suggested as responsible for possible cardiac abnormalities in models of obesity, among them β-adrenergic system, an important mechanism of regulation of myocardial contraction and relaxation. The objetive of present study was to evaluate the . Thirty-day-old male Wistar rats were assigned to one of two groups: control (C) and obese (Ob). The C group was fed a standard diet and Ob group was fed cycles of four unsaturated high-fat diets for 15 weeks. The body fat was measured from the sum of the individual fat pad weights and the obesity was defined by adiposity index. Isolated papillary muscle preparation was performed under basal conditions and after inotropic and lusitropic maneuvers. β-adrenergic system was evaluated by using cumulative concentrations of isoproterenol and Western Blot. After 15 weeks, the Ob rats developed higher adiposity index than C rats. Obesity promoted comorbities such as glucose intolerance, insulin resistance, hyperleptinemia, and dyslipidemia; however, were not associated with changes in systolic blood pressure. The cardiac structure results post-death showed that obesity caused cardiac hypertrophy. Furthermore, Ob muscles developed similar baseline data, but myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca2+ was compromised. There were no changes in cardiac function between groups after β-adrenergic stimulation. The obesity was not accompanied by changes in protein expression of Gsα, β1 and β2 adrenergic receptors. In conclusion, the myorcardial dysfunction caused by unsaturated high-fat diet-induced obesity, after 15 weeks, is not related to β-adrenergic system impairment.

scholarly journals Role of High-Mobility Group Box-1 in Liver Pathogenesis

2019 ◽  
Vol 20 (21) ◽  
pp. 5314 ◽  
Author(s):  
Bilon Khambu ◽  
Shengmin Yan ◽  
Nazmul Huda ◽  
Xiao-Ming Yin
Keyword(s):  
Liver Disease ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Sterile Inflammation ◽  
Contributing Factors ◽  
Drug Induced ◽  
Ductular Reaction ◽  
Alcoholic Fatty Liver

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.

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