Impairment in macroautophagy/autophagy flux and inflammasome activation are common characteristics of nonalcoholic steatohepatitis (NASH). Considering the lack of approved agents for treating NASH, drugs that can enhance autophagy and modulate inflammasome pathways may be beneficial. Here, we investigated the novel mechanism of ezetimibe, a widely prescribed drug for hypercholesterolemia, as a therapeutic option for ameliorating NASH. Human liver samples with steatosis and NASH were analyzed. For in vitro studies of autophagy and inflammasomes, primary mouse hepatocytes, human hepatoma cells, mouse embryonic fibroblasts with Ampk or Tsc2 knockout, and human or primary mouse macrophages were treated with ezetimibe and palmitate. Steatohepatitis and fibrosis were induced by feeding Atg7 wild-type, haploinsufficient, and knockout mice a methionine- and choline-deficient diet with ezetimibe (10 mg/kg) for 4 wk. Human livers with steatosis or NASH presented impaired autophagy with decreased nuclear TFEB and increased SQSTM1, MAP1LC3-II, and NLRP3 expression. Ezetimibe increased autophagy flux and concomitantly ameliorated lipid accumulation and apoptosis in palmitate-exposed hepatocytes. Ezetimibe induced AMPK phosphorylation and subsequent TFEB nuclear translocation, related to MAPK/ERK. In macrophages, ezetimibe blocked the NLRP3 inflammasome-IL1B pathway in an autophagy-dependent manner and modulated hepatocyte-macrophage interaction via extracellular vesicles. Ezetimibe attenuated lipid accumulation, inflammation, and fibrosis in liver-specific Atg7 wild-type and haploinsufficient mice, but not in knockout mice. Ezetimibe ameliorates steatohepatitis by autophagy induction through AMPK activation and TFEB nuclear translocation, related to an independent MTOR ameliorative effect and the MAPK/ERK pathway. Ezetimibe dampens NLRP3 inflammasome activation in macrophages by modulating autophagy and a hepatocyte-driven exosome pathway.

Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration.

Since the robotic surgical system was first introduced in 2005, the number of robotic surgery has been gradually increasing in Korea. The proportion of general robotic surgery is relatively higher compared to the western countries, but robotic liver resection is one of the most complex procedures among robotic general surgery. In this article, we introduce the development of robotic liver resection in Korea and describe our standardized techniques. The current data on robotic liver resection in our institute and other centers in Korea are also presented.

Background: The aim of the present study was to compare the prognostic impact of anatomic resection (AR) versus non‐anatomic resection (NAR) on patient survival after resection of a single hepatocellular carcinoma (HCC).Methods: To control for confounding variable distributions, a 1‐to‐1 propensity score match was applied to compare the outcomes of AR and NAR. Among 710 patients with a primary, solitary HCC of <5.0 cm in diameter that was resectable by either AR or NAR from 2003 to 2007 in Japan and Korea, 355 patients underwent NAR and 355 underwent AR of at least one section with complete removal of the portal territory containing the tumor.Results: Overall survival (OS) was better in the AR than NAR group (hazard ratio 1.67, 95% confidence interval 1.28–2.19, P < 0.001) while disease‐free survival showed no significant difference. Significantly fewer patients in the AR than NAR group developed intrahepatic HCC recurrence and multiple intrahepatic recurrences. Patients with poorly differentiated HCC who underwent AR had improved disease‐free survival and OS.Conclusions: Anatomic resection decreases the risk of tumor recurrence and improves OS in patients with a primary, solitary HCC of <5.0 cm in diameter.