Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice.
Alcoholic liver injury is a major public health issue worldwide. Even though the major mechanisms of this disease have been established over the past decades, little is known about genetic susceptibility factors that may predispose individuals who abuse alcoholic beverages to liver damage and subsequent pathological conditions. We hypothesized that a panel of genetically diverse mouse strains may be used to examine the role of endoplasmic reticulum (ER) stress and one-carbon metabolism in the mechanism of interindividual variability in alcoholic liver injury. We administered alcohol (up to 27 mg/kg/d) in a high-fat diet using an intragastric intubation model for 28 days to male mice from 14 inbred strains (129S1/SvImJ, AKR/J, BALB/cJ, BALB/cByJ, BTBR T+tf/J, C3H/HeJ, C57BL/10J, DBA/2J, FVB/NJ, KK/HIJ, MOLF/EiJ, NZW/LacJ, PWD/PhJ, and WSB/EiJ). Profound interstrain differences (more than 3-fold) in alcohol-induced steatohepatitis were observed among the strains in spite of consistently high levels of urine alcohol that were monitored throughout the study. We found that ER stress genes were induced only in strains with the most liver injury. Liver glutathione and methyl donor levels were affected in all strains, albeit to a different degree. The most pronounced effects that were closely associated with the degree of liver injury were hyperhomocysteinemia and strain-dependent differences in expression patterns of one-carbon metabolism-related genes.


CONCLUSIONS
Our data demonstrate that strain differences in alcohol-induced liver injury and steatosis are striking and independent of alcohol exposure and the most severely affected strains exhibit major differences in the expression of ER stress markers and genes of one-carbon metabolism.
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA.
Masato
M
Tsuchiya
Cheng
C
Ji
Oksana
O
Kosyk
Svitlana
S
Shymonyak
Stepan
S
Melnyk
Hiroshi
H
Kono
Volodymyr
V
Tryndyak
Levan
L
Muskhelishvili
Igor P
IP
Pogribny
Neil
N
Kaplowitz
Ivan
I
Rusyn
D000438:Alcohols / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains / Q000378:metabolism*; D019875:One-Carbon Group Transferases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D012720:Severity of Illness Index; D013045:Species Specificity
D000438:Alcohols; D008715:Methionine; D019875:One-Carbon Group Transferases