Abstract
Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and associated with considerable morbidities. Unfortunately, there is no currently available drug established to treat NAFLD. It was recently reported that intraperitoneal administration of taurine-conjugated ursodeoxycholic acid (TUDCA) improved hepatic steatosis in ob/ob mice. We hereby examined the effect of oral TUDCA treatment on hepatic steatosis and associated changes in hepatic gene expression in ob/ob mice. We administered TUDCA to ob/ob mice at a dose of 500 mg/kg twice a day by gastric gavage for 3 weeks. Body weight, glucose homeostasis, endoplasmic reticulum (ER) stress, and hepatic gene expression were examined in comparison with control ob/ob mice and normal littermate C57BL/6J mice. Compared to the control ob/ob mice, TUDCA treated ob/ob mice revealed markedly reduced liver fat stained by oil red O (44.2±5.8% vs. 21.1±10.4%, P<0.05), whereas there was no difference in body weight, oral glucose tolerance, insulin sensitivity, and ER stress. Microarray analysis of hepatic gene expression demonstrated that oral TUDCA treatment mainly decreased the expression of genes involved in de novo lipogenesis among the components of lipid homeostasis. At pathway levels, oral TUDCA altered the genes regulating amino acid, carbohydrate, and drug metabolism in addition to lipid metabolism. In summary, oral TUDCA treatment decreased hepatic steatosis in ob/ob mice by cooperative regulation of multiple metabolic pathways, particularly by reducing the expression of genes known to regulate de novo lipogenesis.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease [1,2,3] and its prevalence ranges from 10–30% of the general population in the United States [1,3,4,5]
The 4-HNE staining was much stronger in the liver of OB-control group than N-control group, which was markedly diminished by Taurine-conjugated ursodeoxycholic acid (UDCA) (TUDCA) treatment (Figure 2)
We show that oral TUDCA treatment effectively improves fatty liver disease in ob/ob mice independent of weight loss; this improvement is accompanied by alterations in gene expression, biological processes, and metabolic pathways in the liver
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease [1,2,3] and its prevalence ranges from 10–30% of the general population in the United States [1,3,4,5]. In a randomized placebo-controlled trial conducted in NASH patients, UDCA revealed only comparable effects to the placebo in terms of serum liver enzyme levels, hepatic steatosis, necroinflammation, and fibrosis [12]. In a very recent study conducted in obese human subjects focused on tissue insulin sensitivity [22], oral TUDCA treatment did not alter intrahepatic triglyceride content. The baseline intrahepatic triglyceride content of the subjects in TUDCA treatment group was only modestly increased (8.2%). It remains inconclusive whether oral administration of TUDCA reveals similar effects to parenteral administration in terms of improving hepatic steatosis. Since orally administrated TUDCA is absorbed via active transport in the terminal ileum and undergoes a significant hepatic first pass effect and enterohepatic circulation [23,24], the working mechanism of orally administrated TUDCA may be different from that of intraperitoneally injected TUDCA [21]
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