ER stress induces NLRP3 inflammasome activation and hepatocyte death.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1ß secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1ß secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

Evolution of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome after bariatric surgery: a comparative study between gastric bypass and sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) for morbid obesity is gaining in popularity as it offers several advantages over laparoscopic Roux-en-Y gastric bypass (LRYGBP), but comparative data between these two procedures have rarely been reported. METHODS: This case control study compared the incidence of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome in 30 patients undergoing LRYGBP and 30 patients undergoing LSG, matched for age, sex, body mass index (BMI), and glycosylated hemoglobin (HbA1c). RESULTS: At 1-year after surgery, the percent of excess weight loss was 67.8 ± 20.9 for LRYGBP and 61.6 ± 19.4 for LSG. Patients undergoing LRYGBP showed significantly lower plasma levels of C-reactive protein (3.3 ± 2.7 mg/dL vs. 5.3 ± 3.9 mg/dL; P < 0.05), waist circumference (97.4 ± 16.0 vs. 105.5 ± 14.7 cm; P < 0.05), total cholesterol (4.6 ± 1.0 vs. 5.7 ± 0.9 mmol/L; P < 0.01) and LDL cholesterol (2.6 ± 0.8 vs. 3.6 ± 0.8 mmol/L; P < 0.01). Insulin resistance (HOMA index 1.6 ± 1.0 after LRYGBP vs. 2.3 ± 2.4 after LSG), resting energy expenditure (1666.7 ± 320.5 after LRYGBP vs. 1600.4 ± 427.3 Kcal after LSG) and remission of metabolic syndrome (92.9% after LRYGBP vs. 80% after LSG) were not different between the two groups. CONCLUSION: In this study, patients undergoing LRYGBP demonstrated significantly improved lipid profiles, decreased systemic low-grade inflammation compared with those undergoing LSG at 1-year follow-up.

Mycophenolate mofetil monotherapy for severe side effects of calcineurin inhibitors following liver transplantation.

Withdrawal of calcineurin inhibitors (CNI) followed by mycophenolate mofetil (MMF) monotherapy after liver transplantation (LT) remains controversial due to the increased risk of acute rejection and graft loss. The aim of the present study, performed in a large cohort of liver-transplanted patients with severe CNI-induced side effects, was to assess renal function recovery, and safety in terms of liver function, of complete CNI withdrawal and replacement by MMF monotherapy. Fifty-two patients treated with MMF monotherapy for CNI-induced toxicity were analyzed. Mean estimated glomerular filtration rate (eGFR) increased significantly during the period of MMF monotherapy, from 37 +/- 10 to 44.7 +/- 15 mL/min/1.73 m(2) at 6 months (p = 0.001) corresponding to a benefit of +17.4% in renal function. eGFR stabilized or improved in 86.5%, 81% and 79% of cases, and chronic renal dysfunction worsened in 13.5%, 19% and 21% of cases, at 6, 12 and 24 months after CNI withdrawal, respectively. Only two patients experienced acute rejection. MMF monotherapy may be efficient at reversing/stabilizing CRD, and appears relatively safe in terms of liver graft function in long-term liver-transplanted patients. However, clinicians must bear in mind the potential risk of rejection and graft loss, and should be very cautious in the management of such 'difficult-to-treat patients'.