The Efficacy of Tofogliflozin on Metabolic Dysfunction-Associated Fatty Liver Disease

The increasing number of patients with fatty liver disease is a major health problem. Fatty liver disease with metabolic dysfunction has been recognized as nonalcoholic fatty liver disease (NAFLD). Although there is no standard therapy for NAFLD, previous reports support the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on NAFLD. Recently, fatty liver disease with metabolic dysfunction was proposed to be defined as a novel concept, “metabolic associated fatty liver disease (MAFLD)”, and it was proposed that new criteria for MAFLD diagnosis be established. To clarify the effect of SGLT2 inhibitors on MAFLD, we analyzed the efficacy of tofogliflozin in patients with MAFLD. We conducted a single-center, retrospective study to evaluate the efficacy of tofogliflozin in patients with MAFLD treated at Kyushu University Hospital between 2017 and 2019. Tofogliflozin was used to treat 18 patients with MAFLD. To determine the efficacy of tofogliflozin, we evaluated glucose metabolism, insulin resistance, liver injury, hepatic steatosis, and body composition three and six months after drug initiation. Although our study was a preliminary study because of some limitations (e.g., retrospective, observational, single-arm study, small sample size), we show that tofogliflozin could improve liver injury in patients with MAFLD by improving glucose metabolism and insulin resistance without causing muscle loss.

Tuberculosis Arthritis Genu Sinistra with Drug-Induced Liver Injury, COVID 19 Confirmed

Background. Tuberculosis is still a significant health problem, especially in developing countries. Although pulmonary tuberculosis is the most common form of the disease, extrapulmonary tuberculosis also contributes significantly to morbidity and mortality. 10-15% of extrapulmonary cases are due to tuberculous arthritis. The following is a case report of a 36-year-old woman with a diagnosis of genu Sinistra tuberculosis arthritis and drug-induced hepatotoxic injury due to OAT. Case presentation. A woman, 36 years old, Muslim, addresses Banyuasin. The patient is a housewife, treated at Dr. Moh Hoesin General Hospital since October 11, 2021. The main complaint in the form of pain in the left knee has been getting worse since 1 week before being admitted to the hospital. 4 months before admission the hospital, the patient complained of left knee pain, the pain felt like being stabbed, coming and going, especially when walking. In this patient, there was a complaint of nausea that was felt in the pit of the stomach. The results of laboratory examinations showed an increase in the transaminase enzyme and hyperuricemia, so it was suspected that the patient had DILI due to OAT drugs. Hepatocyte death in DILI can occur through two processes, namely processes mediated by apoptosis or necrosis. In apoptosis, cell shrinkage and fragmentation occur into small pieces with the cell membrane intact. These fragments are cleared by phagocytosis and generally do not stimulate the host immune response. Conclusion. A patient diagnosed with arthritis tuberculosis genu Sinistra with Drug-Induced Liver Injury and Confirmed COVID 19.

Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.

The Protective Effects of a Modified Xiaohua Funing Decoction against Acute Liver Failure in Mice Induced by D-Gal and LPS

Objective. The aim of this study was to evaluate the effects of a modified Xiaohua Funing decoction (Xfd) on acute liver failure (ALF) and determine whether the protective mechanisms are related to alterations in the gut microbiota. Methods. An animal model of ALF was induced by intraperitoneal injection of D-galactosamine (D-Gal, 0.5 g/kg) and lipopolysaccharide (LPS, 100 μg/kg). Male BALB/c mice were randomly divided into the following 4 groups: the control group (saline, Con), model group (D-Gal/LPS, Mod), silymarin pretreatment group (200 mg/kg, Sil), and modified Xfd pretreatment group (650 mg/kg, Xfd). The Sil and Xfd groups received the respective intervention orally for 14 days and 2 h before D-Gal/LPS treatment. The liver injury markers included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and liver histology. 16S rRNA gene sequencing was performed to assess the effects on the caecum content. Results. D-Gal/LPS treatment caused severe ALF, illustrating that the ALF model was successfully established. The administration of Sil and Xfd greatly reduced the serum ALT and AST levels and improved the pathological signs of liver injury. However, no significant difference was found between the two groups. In contrast to the Mod group, the Sil and Xfd groups showed a shift toward the Con group in terms of the gut microbiota structure. The abundances of Firmicutes and Bacteroidetes and the Bacteroidetes/Firmicutes ratio in the Mod group significantly differed from those in the Con group. The Sil and Xfd groups showed restoration of the disordered microbiota. Significantly increased relative abundances of Lachnospiraceae_NK4A136_group and Candidatus_Saccharimonas and a markedly decreased Muribaculaceae abundance were found in the Sil and Xfd mice compared with those in the Mod mice ( P < 0.01 , P < 0.05 ). Interestingly, a negative correlation was observed between the abundances of the gut microbiota constituents, specifically Clostridia_UCG-014, and ALT and AST levels. Conclusion. In summary, our results indicate that Xfd may protect the liver and modify the gut microbiota in ALF mice.

ADAM Metalloproteinase Domain 17 Regulates Cholestasis-Associated Liver Injury and Sickness Behavior Development in Mice

Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.

FPS-ZM1 Alleviates Circulating Indices of Liver Injury in Diet-Induced Type 2 Diabetic Mice

Despite dietary/lifestyle modifications as well as glycemic and lipid control, non-alcoholic fatty liver disease (NAFLD) imposes a considerable risk to the patients by advancing to non-alcoholic steatohepatitis (NASH). The present investigation aims to evaluate the protective potential of FPS-ZM1, a selective inhibitor for advanced glycation end products (RAGE), against circulating indices of liver injury in high fat diet-induced diabetic mice. FPS-ZM1 at 0.5. 1, and 2 mg/kg (orally) was administered for 2 months, starting 4 months after provision of the high-fat diet. Tests for glucose homeostasis, liver injury markers, and hepatic/plasma miR-21 expressions were performed. FPS-ZM1 attenuated diabetes-induced elevations in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLD), and alpha glutathione-S-transferase (α-GST) as well as alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). It also decreased diabetes-associated elevations in serum ferritin and plasma cytokeratin 18 fragments. Additionally, FPS-ZM1 down-regulated elevated expressions of miR-21 in the liver and plasma of diabetic mice. These findings highlight the benefits of FPS-ZM in alleviating liver injury in mice evoked by high-fat diet-induced type 2 diabetes and suggest FPS-ZM1 as a new potential adjunct to the conventional diet/lifestyle modification and glycemic control in diabetics.