Ethanol and High Cholesterol Diet Causes Severe Steatohepatitis and Early Liver Fibrosis in Mice
| Autor: | Monika Gooz, Venkat K. Ramshesh, Rick G. Schnellmann, Zhi Zhong, John J. Lemasters, Yasodha Krishnasamy |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
lcsh:Medicine Pathology and Laboratory Medicine Biochemistry chemistry.chemical_compound 0302 clinical medicine Fibrosis polycyclic compounds Medicine and Health Sciences lcsh:Science reproductive and urinary physiology Liver injury Multidisciplinary Chemistry Organic Compounds Liver Diseases Fatty liver Lipids 3. Good health Cholesterol Hyperlipidemia Physical Sciences Liver Fibrosis 030211 gastroenterology & hepatology lipids (amino acids peptides and proteins) Research Article medicine.medical_specialty endocrine system Immunoblotting Hypercholesterolemia Molecular Probe Techniques Gastroenterology and Hepatology Research and Analysis Methods High cholesterol 03 medical and health sciences Signs and Symptoms Diagnostic Medicine Internal medicine mental disorders medicine Molecular Biology Techniques Molecular Biology Nutrition Ethanol lcsh:R Organic Chemistry Chemical Compounds Biology and Life Sciences medicine.disease Diet Fatty Liver 030104 developmental biology Endocrinology Alcohols lcsh:Q Steatosis Steatohepatitis Hepatic fibrosis Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 9, p e0163342 (2016) |
| ISSN: | 1932-6203 |
| Popis: | Background and Aim Because ethanol consumption is commonly associated with a high cholesterol diet, we examined whether combined consumption of ethanol and high cholesterol increases liver injury and fibrosis. Methods Male C57BL/6J mice were fed diets containing: 1) 35% of calories from corn oil (CTR), 2) CTR plus 0.5% (w/v) cholesterol (Chol), 3) CTR plus ethanol (27% of calories) (EtOH), or 4) EtOH+Chol for 3 months. Results In mice fed Chol or EtOH alone, ALT increased to ~160 U/L, moderate hepatic steatosis occurred, and leukocyte infiltration, necrosis, and apoptosis increased modestly, but no observable fibrosis developed. By contrast in mice fed EtOH+Chol, ALT increased to ~270 U/L, steatosis was more extensive and mostly macrovesicular, and expression of proinflammatory molecules (HMGB-1, TLR4, TNFα, ICAM-1) and leukocyte infiltration increased substantially. Necrosis and apoptosis also increased. Trichrome staining and second harmonic generation microscopy revealed hepatic fibrosis. Fibrosis was mostly sinusoidal and/or perivenular, but in some mice bridging fibrosis occurred. Expression of smooth muscle α-actin and TGF-β1 increased slightly by Chol, moderately by EtOH, and markedly by EtOH+Chol. TGF-β pseudoreceptor BAMBI increased slightly by Chol, remained unchanged by EtOH and decreased by EtOH+Chol. MicroRNA-33a, which enhances TGF-β fibrotic effects, and phospho-Smad2/3, the down-stream signal of TGF-β, also increased more greatly by EtOH+Chol than Chol or EtOH. Metalloproteinase-2 and -9 were decreased only by EtOH+Chol. Conclusion High dietary cholesterol and chronic ethanol consumption synergistically increase liver injury, inflammation, and profibrotic responses and suppress antifibrotic responses, leading to severe steatohepatitis and early fibrosis in mice. |
| Databáze: | OpenAIRE |
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