Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

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.

The different effects of psyllium husk and orlistat on weight control, the amelioration of hypercholesterolemia and non-alcohol fatty liver disease in obese mice induced by a high-fat diet

“…After entering the gallbladder, BAs enter the duodenum of the large papilla with bile excretion; (2) Intestinal flora: The intestinal flora reacts with BA, for example, by converting primary BA into secondary BAs; 66 (3) The amount of BA that is reabsorbed by the intestine. 67 CA and CDCA are two major BAs produced by cholesterol metabolism in the liver. These two bile acid convert to DCA, LCA, MCA, UDCA, and HDCA as previously summarised.…”

“…66 (3) The amount of BAs that is reabsorbed by the intestine. 67 CA and CDCA are two major BAs produced by cholesterol metabolism in the liver. These two bile acids are converted into DCA, LCA, MCA, UDCA, and HDCA as previously summarised.…”

Inflammation drives pathogenesis of early intestinal failure-associated liver disease

“…In animal models of NAFLD/NASH, simvastatin reduces liver inflammation and fibrosis, and suppresses hepatic stellate cell activation 34 , 35 . In a murine model of NASH, atorvastatin inhibited intestinal apical sodium-dependent bile salt transporter-mediated reabsorption of bile acids, stearoyl-coenzyme A desaturase-1 (key lipogenesis gene), and NF-kB signaling 36 . Indirect PPARα induction by statin treatment with increased fatty acid oxidation is a proposed mechanism of hepatoprotection against NASH 37 , 38 .…”

Nigakinone alleviates DSS‐induced experimental colitis via regulating bile acid profile and FXR/NLRP3 signaling pathways

“…In the intestine, FXR controls the absorption of BA through the regulation of the expression of four important transporters, including ASBT, IBABP, OSTα, and OSTβ, which are responsible for the transport of BA from the intestine to the portal system (Molinaro & Marschall, 2022). Among them, ASBT was negatively regulated by FXR via the FXR‐FGF15/SHP axis (Sun et al, 2021) and suppressed by the proinflammatory factors (such as IL‐1, TNF‐α and et al) (Lastuvkova et al, 2021). In this study, down‐regulation of ASBT expression during the low FXR expression in colitis is probably related to the inflammatory environment in colitis, and this result is consistent with existing reports (Hou et al, 2018).…”