Abstract
Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high–saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl–coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet–fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide, affecting approximately 30% to 40% of men and 15% to 20% of women
The major form is characterized by simple steatosis, but 30-40% of affected patients develop nonalcoholic steatohepatitis (NASH), which is characterized by steatosis, necroinflammatory changes, and varying degrees of liver fibrosis [1]
The mice fed with the F diet developed histopathological features of NASH with macrovesicular steatosis, ballooning, inflammatory cell infiltration, and fibrosis as demonstrated by hematoxylin and eosin and Sirius red staining (Figure 2)
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide, affecting approximately 30% to 40% of men and 15% to 20% of women. Bile acids (BA) are molecules with a significant function in the pathophysiology of NASH [3] These endogenous amphipathic steroids act through specific receptors, such as the farnesoid X (FXR) (NR1H4), pregnane X (NR1I2), or G-protein-coupled (TGR5 and sphingosine-1-phosphate receptor 2) receptors; inhibit hepatic lipogenesis, gluconeogenesis, and inflammation; and promote energy expenditure. These effects require the intact function of BA transporters to conserve and compartmentalize BA at high concentrations within the intestinal and hepatobiliary tracts and to restrict BA systemic exposure.
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