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Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors are newly developed oral antidiabetic drugs. SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90% of the glucose filtered by the renal glomeruli. SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion. The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood., Aim: To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice., Methods: We analyzed 8-wk-old male obese ( ob/ob ) mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin (3 mg/kg or 10 mg/kg) for 4 wk. We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liver histology, immunoblotting, and reverse transcription-polymerase chain reaction analyses were performed., Results: Hepatic lipid accumulation was significantly ameliorated in ob/ob mice treated with 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective of body weight changes. Ipragliflozin had no appreciable effects on hepatic oxidative stress-related gene expression levels or macrophage infiltration, but significantly reduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozin increased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in the liver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), and fibroblast growth factor-21 (FGF21) were also significantly higher in ipragliflozin-treated ob/ob mice than in untreated ob/ob mice., Conclusion: Our study suggests that the liver steatosis-ameliorating effects of ipragliflozin in ob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: To construct a non-invasive prediction algorithm for predicting non-alcoholic steatohepatitis (NASH), we investigated Japanese morbidly obese patients using artificial intelligence with rule extraction technology., Methods: Consecutive patients who required bariatric surgery underwent a liver biopsy during the operation. Standard clinical, anthropometric, biochemical measurements were used as parameters to predict NASH and were analyzed using rule extraction technology. One hundred and two patients, including 79 NASH and 23 non-NASH patients were analyzed in order to create the prediction model, another cohort with 77 patients including 65 NASH and 12 non-NASH patients were analyzed to validate the algorithm., Results: Alanine aminotransferase, C-reactive protein, homeostasis model assessment insulin resistance, albumin were extracted as predictors of NASH using a recursive-rule extraction algorithm. When we adopted the extracted rules for the validation cohort using a highly accurate rule extraction algorithm, the predictive accuracy was 79.2%. The positive predictive value, negative predictive value, sensitivity and specificity were 88.9%, 35.7%, 86.2% and 41.7%, respectively., Conclusion: We successfully generated a useful model for predicting NASH in Japanese morbidly obese patients based on their biochemical profile using a rule extraction algorithm., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest.

Aim: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice., Methods: We analyzed obese (ob/ob) 8-wk-old male mice that had been randomly divided into two groups of ob/ob mice (n = 16 each) and were treated with 1.5 or 3 mg/kg MK-0626 and two control groups of untreated ob/ob mice and lean littermates (n = 16 each). All mice were fed a normal chow diet with or without MK-0626 for either four or eight weeks. Blood samples were collected, and total hepatectomy was performed., Results: The administration of dietary MK-0626 ameliorated the hepatic lipid accumulation in ob/ob mice treated with 3 mg/kg MK-0626 (3 MK), P < 0.05, vs untreated ob/ob mice (ob/ob). The MK-0626 treatment reduced the serum alanine aminotransferase levels (both treatment groups, P < 0.05 vs ob/ob) and glucoses/insulin levels/calculated HOMA scores (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) and increased the serum adiponectin levels (3 MK, P < 0.05 vs ob/ob) in a dose-dependent manner. The MK-0626 treatment increased the mRNA expression of peroxisome proliferator-activated receptor α/microsomal triglyceride transfer protein (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) but reduced the sterol regulatory element binding transcription factor-1c/fatty acid synthase/stearoyl-CoA desaturase-1 (both treatment groups, P < 0.01 vs ob/ob). The MK-0626 treatment increased the activity of AMP-activated protein kinase (AMPK) (both treatment groups, P < 0.01 vs ob/ob)., Conclusion: MK-0626 could attenuate hepatic steatosis through enhancing AMPK activity, inhibiting hepatic lipogenic gene expression, enhancing triglyceride secretion from liver and increasing serum adiponectin levels.

We devised an extended 72-wk peginterferon-α-2a/ribavirin therapy regimen for the retreatment of highly intractable cases, i.e., 48-wk peginterferon-α-2b/ribavirin therapy-intractable cases. Although 2 cases achieved a rapid virological response to 72-wk peginterferon-α-2a/ribavirin therapy, 1 case failed to achieve a sustained virological response. Although the reason for this difference in the effectiveness of 72-wk peginterferon-α-2a/ribavirin therapy between the cases was unclear, the rebound phenomenon of serum transaminase after 48-wk peginterferon-α-2b/ribavirin therapy and the resultant lower viral load compared to that before 48-wk peginterferon-α-2b/ribavirin therapy might have influenced the treatment outcome. Thus, it may be beneficial to consider the rebound phenomenon of serum transaminase and the changes in viral load resulting from previous interferon-based therapy and then cautiously determine the indication and the timing of the administration of 72-wk peginterferon-α-2a/ribavirin in highly intractable cases. Further studies should be performed to confirm this strategy.

Aim: To predict which chronic hepatitis C patients are likely to be late-responders, we herein investigated the clinical characteristics of null-responders at 36 wk with hepatitis C virus (HCV) genotype Ib and a high viral load during the course of pegylated interferon (Peg-IFN)/ribavirin therapy., Methods: One hundred forty-two patients with genotype Ib HCV and a high viral load were included in this study. Peg-IFNα2b (1.5 μg/kg once a week) and ribavirin (600-1000 mg per day according to body weight) were administered for 48 wk. We defined null-responders as the cases that never cleared serum HCV RNA as determined using RT-PCR until 36 wk. Other patients were defined as responders. We compared the clinical characteristics (age, gender, body mass index, previous treatment) and HCV RNA titer during the therapy between null-responders and responders., Results: The HCV RNA clearance rate was 17.9% (24/134), 46.3% (62/134), 60.6% (86/142), 86.6% (123/142), and 88.0% (125/142) at 4, 8, 12, 24, and 36 wk, respectively. There were 17 patients (12.0%) who were still null-responders at 36 wk. There were no differences in the clinical characteristics between the responders and null-responders except for the titer and decline rates of HCV RNA at 1 wk and 4 wk. The HCV RNA titers at 1 wk and after 4 wk of treatment were significantly higher in the null-responders in comparison to the responders (P <0.01). The serum HCV RNA titers of the responders decreased by 1.3 log after 1 wk of treatment, and 1.6 log after 4 wk of treatment, respectively. On the other hand, the titers of the null responders decreased by only 0.5 log after 1 wk, and 0.7 log after 4 wk of treatment, respectively. The decrease rates of HCV RNA after 1 and 4 wk of treatment were significantly worse for null responders than for the responders (P <0.01)., Conclusion: The HCV RNA titer at 1 wk and 4 wk after initiating treatment may be useful for predicting null-responders to Peg-IFNα2b/ribavirin therapy. However, further investigation is needed to determine the optimal time at which the decision to discontinue the Peg-IFNα2b/ribavirin therapy for null-responders can be made.

Aim: To investigate the in vivo effects of NK2 on liver regeneration after partial hepatectomy (PH)., Methods: Survival after PH was observed with 21 NK2 transgenic mice and 23 wild-type (WT) mice over 10 d. Liver regeneration was analyzed using histology and immunohistochemistry. Expressions of genes were analyzed using Northern blot analysis, immunoprecipitation and immunoblotting, and reverse transcriptase polymerase chain reaction assay. Kaplan-Meier method and the log-rank test were used for analyzing the survival after PH. Differences in the results of immunohistochemistry and percentage of liver regeneration was determined by the Student's t-test., Results: More than half of NK2 transgenic mice died within 48 h after PH. After PH, increased deposition of small lipid droplets in hepatocytes was evident and hepatic proliferation was inhibited in NK2 transgenic mice. The hepatic expression and kinase activity of HGF receptor, c-Met, were unchanged among WT mice and NK2 transgenic mice after PH. The expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in liver tissues were prolonged in NK2 transgenic mice that died after PH., Conclusion: Our findings indicate that over-expression of NK2 inhibits liver regeneration after PH.

Aim: To investigate the precise roles of CAR in CCl(4)-induced acute hepatotoxicity., Methods: To prepare an acute liver injury model, CCl(4) was intraperitoneally injected in CAR+/+ and CAR-/- mice., Results: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl(4)-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR+/+ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR+/+ but not in CAR-/- mice. Thus, CAR activation caused CCl(4) hepatotoxicity while CAR inhibition resulted in partial protection against CCl(4)-induced hepatotoxicity. There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl(4), between CAR+/+ and CAR-/- mice. However, the expression of other CCl(4)-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/- mice. Although the main pathway of CCl(4)-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3A11 in the presence of activator or inhibitor., Conclusion: The nuclear receptor CAR modulates CCl(4)-induced liver injury via induction of CCl(4)-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug-drug interaction even though such drugs themselves are not hepatotoxic.