Genetic and hormonal control of hepatic steatosis in female and male mice.
The etiology of nonalcoholic fatty liver disease is complex and influenced by factors such as obesity, insulin resistance, hyperlipidemia, and sex. We now report a study on sex difference in hepatic steatosis in the context of genetic variation using a population of inbred strains of mice. While male mice generally exhibited higher concentration of hepatic TG levels on a high-fat high-sucrose diet, sex differences showed extensive interaction with genetic variation. Differences in percentage body fat were the best predictor of hepatic steatosis among the strains and explained about 30% of the variation in both sexes. The difference in percent gonadal fat and HDL explained 9.6% and 6.7% of the difference in hepatic TGs between the sexes, respectively. Genome-wide association mapping of hepatic TG revealed some striking differences in genetic control of hepatic steatosis between females and males. Gonadectomy increased the hepatic TG to body fat percentage ratio among male, but not female, mice. Our data suggest that the difference between the sexes in hepatic TG can be partly explained by differences in body fat distribution, plasma HDL, and genetic regulation. Future studies are required to understand the molecular interactions between sex, genetics, and the environment.
Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA FNorheim@mednet.ucla.edu JLusis@mednet.ucla.edu.
Frode
F
Norheim
Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA.
Simon T
ST
Hui
Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA.
Emre
E
Kulahcioglu
Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA.
Margarete
M
Mehrabian
Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA.
Rita M
RM
Cantor
Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA.
Calvin
C
Pan
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI.
Brian W
BW
Parks
Department of Medicine, Division of Cardiology, University of California at Los Angeles, Los Angeles, CA FNorheim@mednet.ucla.edu JLusis@mednet.ucla.edu.
Aldons J
AJ
Lusis
D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006728:Hormones / Q000235:genetics / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D008075:Lipoproteins, HDL / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012727:Sex Characteristics; D014280:Triglycerides / Q000235:genetics*
C034396:HDL-triglyceride; D006728:Hormones; D008075:Lipoproteins, HDL; D014280:Triglycerides
genetics; gonadectomy; hormones; insulin; nonalcoholic fatty liver disease; nutrition/lipids; obesity