Genetic and hormonal control of hepatic steatosis in female and male mice

Abstract

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.

Keywords: genetics; gonadectomy; hormones; insulin; nonalcoholic fatty liver disease; nutrition/lipids; obesity.

Fig. 1.

Genetic variation in hepatic TG accumulation among female inbred mouse strains. A: Hepatic TG in 100 female mouse strains after 8 weeks of HF/HS feeding. Results are presented as mean ± SD. B–D: Correlation of hepatic TG with hepatic total cholesterol (TC) (B), hepatic unesterified cholesterol (UC) (C), and hepatic phospholipids (PL) (D). r, biweight midcorrelation; p, P value.

Fig. 2.

Large variation in hepatic TG accumulation between the sexes. Hepatic TG in female (red) and male (blue) mice after 8 weeks of HF/HS feeding. Results are presented as mean ± SD.

Fig. 3.

Pathway enrichment analysis using the top 1,000 most correlated genes with hepatic TG. GO pathways reaching significance for female (red) and male (blue) after Bonferroni correction are shown (P < 0.05). GO analyses were performed using the DAVID database. The P value is shown as –log 10 of p.

Fig. 4.

Differences in major loci contributing to genetic control of hepatic TG between the sexes. A, B: Manhattan plot showing the significance (–log 10 of p) of all SNPs and hepatic TG after 8 weeks of HF/HS feeding in female (A) and male (B) mice. Genome-wide significance cut-off (3.46 × 10⁻⁶) is shown by the red line.

Fig. 5.

Effect of gonadal hormones on hepatic TG accumulation. A, B: Hepatic TG in female (A) and male (B) strains (C3H/HeJ, C57BL/6J, and DBA/2J) after ovariectomy/gonadectomy, sham operated, or untreated controls, and being maintained on chow or HF/HS diet (n = 3–4 mice per strain, group, and sex). C, D: Hepatic TG normalized to percentage body fat (TG/BF%) in female (C) and male (D) strains (C3H/HeJ, C57BL/6J, and DBA/2J) after ovariectomy/gonadectomy, sham operated, or untreated controls, and being maintained on chow or HF/HS diet (n = 3-4 mice per strain, group and sex). (E-F) Hepatic TG/BF% in all (E) female and (F) male strains after ovariectomy/gonadectomy, sham operated or untreated controls, and being maintained on chow or HF/HS diet (n = 10–12 mice per group and sex). Results are presented as mean ± SD. Statistical differences between groups were tested using unpaired two-tailed Student’s t-tests. *P < 0.05 and **P < 0.01 between the gonadectomized group and both controls (sham operated and untreated controls).