Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis - PubMed (original) (raw)

Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis

Christopher Savard et al. Hepatology. 2013 Jan.

Abstract

The majority of patients with nonalcoholic fatty liver disease (NAFLD) have "simple steatosis," which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%-30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction.

Conclusion: Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice.

Copyright © 2012 American Association for the Study of Liver Diseases.

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Conflict of interest statement

Potential conflict of interest: Nothing to report.

Figures

Fig. 1

Fig. 1

Dietary consumption and percent body-weight change during the 30-week experiment. Mice on the HFHC diet consumed fewer calories, but gained more weight, than mice on the isocaloric HF diet. There was no difference between mice on the HC diet and mice on the control diet in the amount of food consumed or in weight change during the experiment. Therefore, the addition of dietary cholesterol only caused weight gain in the presence of increased dietary fat.

Fig. 2

Fig. 2

Comparison* of experimental diets with respect to liver weight and lipid composition. *We calculated P values only for two comparisons: the HFHC versus the HF group and the HC versus the control group. Only P values <0.05 are shown.

Fig. 3

Fig. 3

Comparison* of experimental diets with respect to (A) plasma laboratory tests and (B) fecal lipid composition. *We calculated _P_values only for two comparisons: the HFHC versus the HF group and the HC versus the control group. Only P values <0.05 are shown.

Fig. 4

Fig. 4

Comparison* of experimental diets with respect to (A) liver mRNA expression and (B) intra-abdominal adipose tissue mRNA expression. *We calculated P values only for two comparisons: the HFHC versus the HF group and the HC versus the control group. Only P values <0.05 are shown.

Fig. 5

Fig. 5

Mouse liver sections obtained after 30 weeks on each of the four experimental diets (control, HC, HF, HFHC) and stained with hematoxylin and eosin, Sirius Red (viewed with normal or polarized light), and Masson’s trichrome. Sections demonstrate the following histological features: (A) control diet: healthy liver histology; (B) HC diet: mild to moderate steatosis with little inflammatory infiltrate and no fibrosis (i.e., simple steatosis); (C) HF diet: mild to moderate steatosis with little inflammatory infiltrate and no fibrosis (i.e., simple steatosis); and (D) HFHC diet: severe steatosis with substantial inflammatory infiltrate and perisinusoidal, “chickenwire” fibrosis consistent with NASH.

Comment in

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