Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice - PubMed (original) (raw)

Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice

Valentina Volynets et al. J Lipid Res. 2010 Dec.

Abstract

Fructose intake is being discussed as a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Bile acids have been shown to modulate energy metabolism. We tested the effects of bile acids on fructose-induced hepatic steatosis. In C57BL/6J mice treated with a combination of chenodeoxycholic acid and cholic acid (100 mg/kg body weight each) while drinking water or a 30% fructose solution for eight weeks and appropriate controls, markers of hepatic steatosis, portal endotoxin levels, and markers of hepatic lipogenesis were determined. In mice concomitantly treated with bile acids, the onset of fructose-induced hepatic steatosis was markedly attenuated compared to mice only fed fructose. The protective effects of the bile acid treatment were associated with a downregulation of tumor necrosis factor (TNF)α, sterol regulatory element-binding protein (SREBP)1, FAS mRNA expression, and lipid peroxidation in the liver, whereas hepatic farnesoid X receptor (FXR) or short heterodimer partner (SHP) protein concentration did not differ between groups fed fructose. Rather, bile acid treatment normalized occludin protein concentration in the duodenum, portal endotoxin levels, and markers of Kupffer cell activation to the level of water controls. Taken together, these data suggest that bile acids prevent fructose-induced hepatic steatosis in mice through mechanisms involving protection against the fructose-induced translocation of intestinal bacterial endotoxin.

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Figures

Fig. 1.

Effect of chronic consumption of 30% fructose solution and bile acids on the lipid accumulation in the liver. A: Representative photomicrographs of the hematoxylin and eosin (200×) as well as Oil Red O staining (400×) of liver sections. B and C: Quantitative analysis of Oil Red O staining and hepatic triglyceride content. Data are shown as means ± SEM (n = 5–6) and are normalized to percent of control. a_P_ < 0.05 compared with mice fed water; b_P_ < 0.05 compared with mice fed water + bile acids; d_P_ < 0.05 compared with mice fed fructose solution + bile acids. C, water; BA, bile acid; F, 30% fructose solution.

Fig. 2.

Effect of chronic consumption of 30% fructose solution and bile acids on the hepatic lipid peroxidation and TNFα mRNA levels in liver. A: Representative photomicrographs of immunostaining of 4-HNE adducts (200×) in liver sections. 4-HNE adducts are brown. B: Densitometric analysis of 4-HNE adduct staining. C: Relative hepatic TNFα mRNA expression as determined by realtime RT-PCR. Data for TNFα are normalized to β-actin. Data are shown as means ± SEM (n = 5–6) and are normalized to percent of control. a_P_ < 0.05 compared with mice fed water; b_P_ < 0.05 compared with mice fed water + bile acids; d_P_ < 0.05 compared with mice fed fructose solution + bile acids. C, water; BA, bile acid; F, 30% fructose solution; 4-HNE, 4-Hydroxynonenal; TNF, tumor necrosis factor.

Fig. 3.

Effect of chronic consumption of 30% fructose solution and bile acids on nuclear protein concentration of SHP and FXR in the liver. A: Representative Western blot of SHP and histone H3 (3H1) as well as quantitative analysis of blots. B: Representative Western blot of FXR and histone H3 (3H1) as well as quantitative analysis of blots. Data are shown as means ± SEM (n = 5–6) and are normalized to percent of control. a_P_ < 0.05 compared with mice fed water. C, water; BA, bile acid; F, 30% fructose solution; FXR, farnesoid X receptor; SHP, short heterodimer partner.

Fig. 4.

Effect of chronic consumption of 30% fructose solution and bile acids on occludin concentration in the duodenum and portal endotoxin levels. A: Representative Western blots of occludin and quantitative analysis of blots. Data for occludin were normalized to β-actin. B: Portal endotoxin concentration. Data are shown as means ± SEM (occludin, n = 5–6; endotoxin, n = 3–6) and are normalized to percent of control. a_P_ < 0.05 compared with mice fed water; b_P_ < 0.05 compared with mice fed water + bile acids. C, water; BA, bile acid; F, 30% fructose solution.

Fig. 5.

Effect of chronic consumption of 30% fructose solution and bile acids on hepatic MyD88, IRF3, and IRF7 as well as iNOS levels. Expression of (A) MyD88, (B) IRF7, (C) IRF3, and (D) iNOS determined by realtime RT-PCR. Expression levels were normalized to β-actin expression. Data are expressed as means ± SEM (n = 4–6).a_P_ < 0.05 compared with mice fed water; b_P_ < 0.05 compared with mice fed water + bile acids; d_P_ < 0.05 compared with mice fed fructose solution + bile acids. C, water; BA, bile acid; F, 30% fructose solution; IRF3/7, interferon regulatory factor 3 or 7; MyD88, myeloid differentiation factor; iNOS, inducible nitric oxide synthase.

Fig. 6.

Effect of chronic consumption of 30% fructose solution and bile acids on number of bacteria in the small intestine. A: Representative pictures of FISH. B: Quantitative analysis of FISH. Data are expressed as means ± SEM (n = 4–6). C, water; BA, bile acid; F, 30% fructose solution; FISH, fluorescent in situ hybridization.

References

1. Clark J. M. 2006. The epidemiology of nonalcoholic fatty liver disease in adults. J. Clin. Gastroenterol. 40(Suppl. 1): S5–S10. - PubMed
1. Yang S. Q., Lin H. Z., Mandal A. K., Huang J., Diehl A. M. 2001. Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology. Hepatology. 34: 694–706. - PubMed
1. Adams L. A., Lymp J. F., St S. J., Sanderson S. O., Lindor K. D., Feldstein A., Angulo P. 2005. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 129: 113–121. - PubMed
1. Ouyang X., Cirillo P., Sautin Y., McCall S., Bruchette J. L., Diehl A. M., Johnson R. J., Abdelmalek M. F. 2008. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J. Hepatol. 48: 993–999. - PMC - PubMed
1. Ackerman Z., Oron-Herman M., Grozovski M., Rosenthal T., Pappo O., Link G., Sela B. A. 2005. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension. 45: 1012–1018. - PubMed

Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice - PubMed (original) (raw)