Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice

Abstract

Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.

Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

“…As also reported elsewhere [12,14,15], foz/foz mice fed with a HFD for 12 weeks are overtly obese, hyperglycemic, and glucose intolerant compared to chow-fed (normal diet) littermates ( Fig. 1a-c).…”

“…NRG4 protein levels in BAT were measured using an ELISA kit (MyBiosource). Total liver lipids were extracted with methanol and chloroform and quantified using the vanillin phosphoric acid reaction [14].…”

Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non‐alcoholic fatty liver disease

“…TUDCA, an amphiphilic bile acid, is the taurine conjugate form of ursodeoxycholic acid (UDCA). It is known as a chemical chaperone against ER stress (Ozcan et al ., ) and has been recently reported to reduce liver steatosis in several studies (Choi et al ., ; Legry et al ., ). In our present study, we demonstrated the effectiveness of TUDCA in alleviating hepatic steatosis and inflammation, as well as improving obesity and insulin resistance.…”

Mechanism of ER Stress and Inflammation for Hepatic Insulin Resistance in Obesity

“…This correlation between ER stress and inflammation can be found in previous studies on the mechanism [73] investigated the effect of treatment with the ER stress inducer tunicamycin, or conversely, with the ER protectant tauroursodeoxycholic acid in foz/foz mice, and found that the ER protectant failed to improve glucose intolerance, hepatic inflammation and apoptosis. It is still too early to conclude that ER stress and inflammation are the major mechanisms underlying obesity-induced hepatic insulin resistance because of a lack of sufficient evidence, although we can hypothesize that ER stress and inflammation play key roles in the mechanism based on the aforementioned.…”