Hepatic gene expression and lipid parameters in complement C3−/− mice that do not develop ethanol-induced steatosis

• Published in: Journal of hepatology 2007-05, Vol.46 (5), p.907-914
• Main Authors: Bykov, Igor, Jauhiainen, Matti, Olkkonen, Vesa M, Saarikoski, Sirkku T, Ehnholm, Christian, Junnikkala, Sami, Väkevä, Antti, Lindros, Kai O, Meri, Seppo
• Format: Article
• Language: English
• Subjects: Addictive behaviors; Adiponectin - metabolism; Adult and adolescent clinical studies; Alcoholic liver steatosis; Alcoholism; Alcoholism and acute alcohol poisoning; Alternative complement pathway; Animals; Biological and medical sciences; Biosynthetic Pathways - drug effects; C3 deficiency; Complement C3 - deficiency; Complement C3 - genetics; Complement C3 - metabolism; Dietary Fats - administration & dosage; Ethanol; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - pathology; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Hepatic gene expression; Interleukin-10 - blood; Lipid Metabolism; Lipoproteins; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - genetics; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse microarray; Oligonucleotide Array Sequence Analysis; Other diseases. Semiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; RNA - genetics; Toxicology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2006.11.020

Background/Aims Fatty infiltration initiates alcohol-induced liver changes and complement component C3 affects lipid metabolism. We recently observed that ethanol-induced steatosis seen in normal (C3+/+ ) mice was absent in livers of C3-deficient (C3−/− ) mice. To understand the underlying molecular mechanisms we analyzed lipid parameters and liver gene expression profiles in these mice. Methods A Western-type high-fat diet with ethanol or carbohydrates (control) was fed for 6 weeks to C3+/+ and C3−/− mice. Serum and liver lipid parameters were analyzed and liver mRNA expression patterns studied by micro-array analysis and RT-PCR. Results In both genotypes ethanol markedly reduced serum cholesterol, apolipoprotein A-I, phospholipid transfer protein activity and hepatic mRNA levels of fatty acid-binding proteins and fatty acid β-oxidation enzymes. In contrast, exclusively in C3−/− mice, ethanol treatment increased serum and liver adiponectin levels but down-regulated transcripts of lipogenic enzymes, adiponectin receptor 2 and adipose differentiation-related protein and up-regulated phospholipase D1. Conclusions We propose that these ethanol-induced alterations observed exclusively in C3−/− mice contribute to protection against fatty infiltration and subsequent inflammatory processes in the liver of these mice. The results suggest important cross-talk between complement factor C3 and lipid regulators in ethanol-induced steatosis.