Changes in Hepatic Gene Expression upon Oral Administration of Taurine-Conjugated Ursodeoxycholic Acid in ob/ob Mice

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.

A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2α Phosphorylation in Obesity

“…In contrast, activation levels of JNK in liver of Pkr −/− ob/ob mice were significantly lower than those detected in Pkr +/+ ob/ob controls. Similarly, the increased eIF2α phosphorylation seen in the liver of ob/ob mice in numerous independent studies (Ozcan et al, 2004; Sreejayan et al, 2008; Tsutsumi et al, 2011; Yang et al, 2010) was significantly reduced to levels close to lean controls upon loss of PKR (Figure 5G). Of note, activation of PERK, the ER resident eIF2α kinase, remained elevated in liver of Pkr −/− ob/ob mice (Figure S4D).…”

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

“…Because lipotoxicity impairs ER function and leads to a prolonged unfolded protein response, which can engage stress and inflammatory pathways, it may also be considered for potential intervention strategies. The use of agents that alleviate ER stress, such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid, has been tested in metabolic contexts with beneficial results on liver and CNS function (153,(233)(234)(235). TUDCA treatment in experimental models of acute pancreatitis and ischemia reperfusion in liver also demonstrated decreased JNK activity along with attenuated inflammatory responses (236,237).…”

Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes

“…[4][5][6][7][8] In addition, modulation of ER stress improved hepatic steatosis with a restoration of glucose homeostasis and insulin sensitivity in the diabetic mouse. 9,10 A recent epidemiological study using data from the National Health and Nutrition Examination Survey revealed that uric acid was associated with NAFLD independently of metabolic syndrome. 11 Additional studies have shown that elevated serum uric acid is an independent predictor of NAFLD.…”