Hepatic gene expression and lipid parameters in complement C3(-/-) mice that do not develop ethanol-induced steatosis.
OBJECTIVE
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 beta-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.
Bykov
Igor
I
National Public Health Institute, Departments of Mental Health and Alcohol Research, Finland.
Jauhiainen
Matti
M
Olkkonen
Vesa M
VM
Saarikoski
Sirkku T
ST
Ehnholm
Christian
C
Junnikkala
Sami
S
Väkevä
Antti
A
Lindros
Kai O
KO
Meri
Seppo
S
D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects; D003176:Complement C3 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D000431:Ethanol; D005235:Fatty Liver, Alcoholic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D016753:Interleukin-10 / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052242:Adiponectin; D003176:Complement C3; D004041:Dietary Fats; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000431:Ethanol; D012313:RNA