Hepatic steatosis is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased with its attendant complications, including metabolic syndrome and non-alcoholic fatty liver disease. Steatotic livers are particularly vulnerable to ischemia/reperfusion injury, resulting in an increased risk of postoperative morbidity and mortality after liver surgery, including liver transplantation. There is growing understanding of the molecular and cellular mechanisms and therapeutic approaches for treating ischemia/reperfusion injury in patients with steatotic livers. This review discusses the mechanisms underlying the susceptibility of steatotic livers to ischemia/reperfusion injuries, such as mitochondrial dysfunction and signal transduction alterations, and summarizes the clinical impact of steatotic livers in the setting of hepatic resection and liver transplantation. This review also describes potential therapeutic approaches, such as ischemic and pharmacological preconditioning, to prevent ischemia/reperfusion injury in patients with steatotic livers. Other approaches, including machine perfusion, are also under clinical investigation; however, many pharmacological approaches developed through basic research are not yet suitable for clinical application.

Rho-kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver-specific ROCK inhibition is required. Here, we tested vitamin A (VA)-coupled liposomes carrying the ROCK inhibitor Y-27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline-deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y-27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VAcoupled liposome accumulation in livers. Liposomal Y-27632 was 100-fold more effective in inhibiting HSC activation than free Y-27632. Liposomal Y-27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y-27632 elicited severe systemic hypotension. We conclude that VA-coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123-131, 2015.

Fatty liver (FL) is associated with development of hepatocellular carcinoma (HCC). However, whether FL itself promotes the progression of HCC is unclear. We recently found that hepatic stellate cells (HSCs) were prominently activated in the steatotic liver. Here, we investigated whether steatotic livers promote HCC progression and whether HSCs of steatotic liver are associated with HCC progression. We implanted rat HCC cells into diet-induced steatotic livers in rats via portal vein injection. Thereafter, HSCs and HCC cells were co-implanted subcutaneously into nude rats. Migration and proliferation of HCC cells were measured, and activation of ERK and Akt in these cells was determined by western blotting. Chemokines secreted from HSCs and HCC cells were also evaluated by ELISA. Steatotic livers significantly promoted HCC metastasis compared with nonsteatotic livers. Additionally, co-implantation of HCC cells with HSCs from steatotic livers produced significantly larger tumors in recipient rats as compared to those induced by HCC cells co-implanted with HSCs from normal livers (NLs). HSCs isolated from steatotic livers, compared with HSCs isolated from NLs, secreted greater amounts of interleukin-1a, vascular endothelial growth factor, and transforming growth factor-b. These cytokines may enhance the proliferation and migration of HCC cells by increasing the phosphorylation of ERK and Akt in HCC cells. Moreover, we noted that the Rho-kinase inhibitor deactivated activated HSCs and attenuated HCC progression. In conclusion, the rat steatotic liver microenvironment favors HCC metastasis, and this effect appears to be promoted by activated HSCs in the steatotic liver.Non-alcoholic fatty liver disease (NAFLD) is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased along with its attendant complications, including metabolic syndrome and NAFLD. Recently, there is increasing evidence that NAFLD, including the more aggressive non-alcoholic steatohepatitis (NASH), is associated with hepatocellular carcinoma (HCC).1-3 Diabetes and obesity are established independent Key words: HCC, hepatic stellate cell, fatty liver, Rho-kinase Abbreviations: CDD: choline-deficient diet; CM: conditioned media; DMEM: Dulbecco's modified Eagle's medium; ELISA: enzymelinked immunosorbent assay; FL: fatty liver; FBS: fetal bovine serum; HCC: hepatocellular carcinoma; HGF: hepatocyte growth factor; HSCs: hepatic stellate cells; HSCFL: hepatic stellate cells isolated from fatty liver; HSCNL: hepatic stellate cells isolated from normal liver; HFD: high-fat diet; HIF: hypoxia inducible factor; IL-1a: interleukin-1a; IQGAP1: IQ motif containing GTPase activating protein 1; MMPs: matrix metalloproteinases; MTT: methyl thiazolyl tetrazolium; MAPK: mitogen-activated protein kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatotic hepatitis; NL: normal liver; ROCK: Rho-associated kinase; SASP: senescence-associated secretory phenotype; SDF-1: stromal derive...

Background/Aims: Coagulopathy can cause disseminated intravascular coagulation and posthepatectomy liver failure. Posthepatectomy liver failure predicts a poor prognosis after hepatectomy for hepatocellular carcinoma. Although antithrombin III reduces hypercoagulation, the impact of postoperative antithrombin III administration remains unknown. The aim of this study was to determine whether postoperative antithrombin III administration protects against the development of coagulation disorders. Methods: Data from 164 patients who received antithrombin III and 169 who did following curative hepatectomy for hepatocellular carcinoma were retrospectively collected and analyzed. To overcome bias due to different distributions of covariates for the two groups, a one-to-one match was created using propensity score analysis. After matching, patient outcomes were analyzed. Results: A multivariate analysis of the whole group revealed that antithrombin III activity of <50% on postoperative day 1 was an independent risk factor for posthepatectomy liver failure. After one-to-one matching, the rate of posthepatectomy liver failure was significantly lower in the AT-III-treated group than in the non-AT-III-treated group (16.3% (7/43) vs. 44.2% (19/43), p < 0.01). Conclusions: Antithrombin III may attenuate posthepatectomy liver failure in hepatocellular carcinoma, possibly by suppressing coagulopathy.

The surgical implantation of radiopaque biodegradable biliary stents in biliary surgery represents a new option for duct-to-duct biliary reconstruction. This technique appears to be feasible and safe and is not associated with any significant biliary complications. The advantage of coated biliary stent use is that it may be visualized using abdominal radiography such as CT.