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J Neurogastroenterol Motil. 2025;31(4):477-490.

Age- and Sex-dependent Effects of High-fructose, High-fat Diets on Small Bowel Inflammation and Hepatic Steatosis in F344 Rats.

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제1저자 하성찬 · 교신저자 김나영

PMID 41077749 PMC12527957 DOI 10.5056/jnm24155 IF 3.7 소화기내과
소속 (8)
  1. Department of Health Science and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
  2. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.
  3. Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
  4. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
  5. Department of Medical Device Development, Seoul National University College of Medicine, Seoul, Korea.
  6. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.
  7. Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
  8. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND/AIMS The liver and small bowel are closely interrelated, and their diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) may also be influenced by age and sex. Therefore, this study aims to investigate the effects of age and sex on hepatic steatosis and small bowel inflammation induced by a high-fructose and high-fat diet (HFHFD) in rats.

METHODS Male and female rats, aged 6 weeks (young) and 2 years (aged), were used. The HFHFD groups were provided with a high-fat diet and high-fructose water for 8 weeks. Liver and small bowel tissues were histologically analyzed. Tight junction protein expression in jejunal mucosa was analyzed, and immunohistochemistry was performed to detect claudin-2 (Cldn-2).

RESULTS The histological inflammation scores of the old control groups were higher than those of the young control groups, regardless of sex. The jejunal villus/crypt ratio in the young rats was decreased in the male HFHFD group (P = 0.045). In contrast, in aged rats, the villus/crypt ratio decreased in the female HFHFD group (P = 0.076). Hepatic steatosis was higher for the male HFHFD groups (young, P = 0.003; aged, P = 0.005) and in the aged female HFHFD groups (P = 0.003). The correlation of jejunal inflammation scores with hepatic steatosis (P < 0.001) and Cldn-2 mRNA expression (P = 0.047) was significant, with the highest expression observed in aged female HFHFD rats.

CONCLUSION MASLD may be associated with HFHFD-induced jejunal damage. In addition, the upregulation of Cldn-2 may contribute to MASLD in aged female rats.

Keywords

Age factorsClaudin-2Fatty liverIntestine, smallSex characteristics

Figures

Figure 1
Figure 1 Study flow chart demonstrating each group. 6 wk, young; 2 yr, aged; M, male; F, female; C, control; HFHFD, high-fructose and high-fat diet. n = 6 for all groups except for the 2 yr. M. C group (n = 5).
Figure 2
Figure 2 Body weight change and calorie intake of young (A, B) and aged (C, D) rats. n = 6 for all groups except the aged male control group (n = 5). Mean ± standard error of the mean (SEM), *P < 0.05 compared to the male controls, +P < 0.05 compared to the female controls, and #P < 0.05 compared to the female high-fructose high-fat diet (HFHFD) rats according to Mann–Whitney U test. 6 wk, young; 2 yr, aged; M, male; F, female; C, control. n = 6 for all groups except for the 2 yr. M. C group (n = 5).
Figure 3
Figure 3 Histological analysis of small bowel tissues. H&E stains of the duodenum (A), jejunum (B), and ileum (C) under × 20 magnification. Comparison of all control groups at young and aged (D). Inflammation scores of both male control groups (E) and female control groups (F). Inflammation scores of epithelial damage and inflammatory cell infiltration in the duodenum (G), jejunum (H), and ileum (I). P-values from the Kruskal–Wallis test are shown in the figure. 6 wk, young; 2 yr, aged; M, male; F, female; C, control; HFHFD, high-fructose and high-fat diet; D, duodenum; J, jejunum; I, ileum. Mean ± SEM, Mann–Whitney U test. Inflammatory cell infiltration (red arrows) were observed. Inflammation score of the duodenum: 6 wk. M. C vs 2 yr. M. C, P = 0.005; 6 wk. F. C vs 2 yr. F. C, P = 0.007; 6 wk. F. C vs 6 wk. F. HFHFD, P = 0.007; 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.037. Inflammation score of the jejunum: 6 wk. M. C vs 6 wk. F. C, P = 0.007; 6 wk. F. C vs 2 yr. F. C, P = 0.002; 6 wk. M. C vs 6 wk. M. HFHFD, P = 0.026; 6 wk. F. C vs 6 wk. F. HFHFD, P = 0.007; 2 yr. M. C vs 2 yr. M. HFHFD, P = 0.027; 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.049. Inflammation score of the ileum, 6 wk. M. C vs 2 yr. M. C, P = 0.022; 6 wk. F. C vs 2 yr. F. C, P = 0.007; 6 wk. M. C vs 6 wk. M. HFHFD, P =0.049. n = 6 for all groups except for the 2 yr. M. C group (n = 5).
Figure 4
Figure 4 Histological analysis of jejunum tissue length. H&E stain of the jejunum tissue (A). Villus height (B), crypt depth (C), and villus/crypt ratio (D). 6 wk, young; 2 yr, aged; M, male; F, female; C, control; HFHFD, high-fructose and high-fat diet. Mean ± SEM, Mann–Whitney U test. Villus length of jejunum in the 6 wk. M. HFHFD group showed a decrease compared to that in the 6 wk. M. C group; however, the difference was not significant. Crypt length of the jejunum: 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.028. The villus/crypt ratio significantly decreased in the 6 wk. M. HFHFD group compared to that in the 6 wk. M. C group. The ratio also decreased in the 2 yr. F. HFHFD group compared to that in the 2 yr. F. C group; however, the difference was not significant. n = 6 for all groups except for the 2 yr. M. C group (n = 5).
Figure 5
Figure 5 Histological analysis of liver tissues, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) enzyme activity and enzyme-linked immunosorbent assay (ELISA) results. H&E stains under × 20 magnification (A). Histological steatosis score (B) and fibrosis (E) of the liver. AST (C) and ALT activity (D) in the serum. AST (F) and ALT (G) ELISA results in the serum. P-values from the Kruskal–Wallis test are shown in the figure; Mean ± SEM, Mann–Whitney U test. 6 wk, young; 2 yr, aged; M, male; F, female; C, control; HFHFD, high-fructose and high-fat diet. Liver steatosis (%): 6 wk. M. C vs 6 wk. M. HFHFD, P = 0.003; 6 wk. M. HFHFD vs 6 wk. F. HFHFD, P = 0.003; 6 wk. F. HFHFD vs 2 yr. F. HFHFD, P = 0.004; 2 yr. M. C vs 2 yr. M. HFHFD, P = 0.005; 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.003. Liver steatosis increased in the 2 yr. M. HFHFD group compared to that in the 6 wk. M. HFHFD group; however, the difference was not significant. ALT activity: 6 wk. M. C vs 6 wk. M. HFHFD, P = 0.009; 6 wk. M. HFHFD vs 6 wk. F. HFHFD, P = 0.009; 6 wk. M. HFHFD vs 2 yr. M. HFHFD, P = 0.009. AST activity: 6 wk. M. C vs 6 wk. M. HFHFD, P = 0.009; 6 wk. M. C vs 2 yr. M. C, P = 0.028; 6 wk. M. HFHFD vs 6 wk. F. HFHFD, P = 0.047; 2 yr. M. C vs 2 yr. F. C, P = 0.050. AST activity increased in the 2 yr. F. HFHFD group compared to that in the 2 yr. F. HFHFD group; however, the difference was not significant. Liver Fibrosis score: 6 wk. M. C vs 6 wk. M. HFHFD, P = 0.001; 6 wk. F. C vs 6 wk. F. HFHFD, P = 0.001; 2 yr. M. C vs 2 yr. M. HFHFD, P = 0.001; 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.001. ELISA result of ALT: 6 wk. M. HFHFD vs 6 wk. F. HFHFD, P = 0.025; 6 wk. F. C vs 2 yr. F. C, P = 0.006; 6 wk. F. HFHFD vs 2 yr. F. HFHFD, P = 0.025. n = 6 for all groups except for the 2 yr. M. C group (n = 5).
Figure 6
Figure 6 Expression of tight junction protein mRNA in both male and female rats (A-E) exposed to or not exposed to high-fructose and high-fat diet (HFHFD) in the jejunum mucosa. Mean ± SEM, Mann–Whitney U test. 6 wk, young; 2 yr, aged; M, male; F, female; C, control. Cldn-2: 6 wk. M. HFHFD vs 6 wk. F. HFHFD, P = 0.041; 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.005. Cldn-1: 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.007. Cldn-4: 6 wk. M. HFHFD vs 2 yr. M. HFHFD, P = 0.009; 2 yr. M. HFHFD vs 2 yr. F. HFHFD, P = 0.049. Ocln: 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.049. Zo-1: 2 yr. F. C vs 2 yr. F. HFHFD, P = 0.020. n = 6 for all groups except for the 2 yr. M. C group (n = 5).
Figure 7
Figure 7 Correlation between histological scores and mRNA expression. Steatosis percentage (A), Cldn-2 mRNA expression (B), jejunum villus/crypt ratio (C), and jejunum inflammation score. Steatosis (D), aminotransferase (ALT) enzyme-linked immunosorbent assay (ELISA) result (E), and jejunum villus/crypt ratio. Jejunum villus/crypt ratio (F), steatosis (G), and Cldn-2 mRNA expression. P-value < 0.05 from Spearman’s correlation (A-E). Each line indicates regression. Correlations were analyzed using the Spearman’s rank correlation coefficient method and linear regression analysis. (A) (P < 0.001) and (B) (P = 0.047) showed a positive correlation. (C) (P = 0.002), (D) (P = 0.001) and (E) (P = 0.047) demonstrated a negative correlation. (E) and (F) did not show a significant correlation. 6 wk, young; 2 yr, aged; M, male; F, female; C, control; HFHFD, high-fructose and high-fat diet. n = 6 for all groups except for the 2 yr. M. C group (n = 5).

그림 출처: PubMed Central 공개 논문 (PMC12527957)

Conflict of interest statement

Conflicts of interest: None.

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Journal of neurogastroenterology and motility · ISSN 2093-0879
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