Loss of ERdj5 exacerbates oxidative stress in mice with alcoholic liver disease via suppressing Nrf2.

Alcoholic liver disease is the major cause of chronic liver diseases. Excessive alcohol intake results in endoplasmic reticulum (ER) stress. ERdj5, a member of DNAJ family, is an ER-resident chaperone protein, whose role in alcoholic liver disease remains to be investigated. In this study, we aim to address the effect of ERdj5 on alcoholic liver disease and the underlying mechanism. Hepatic Dnajc10 (ERdj5) mRNA expression was elevated in both human and mouse alcoholic hepatitis. In mice subjected to chronic and binge ethanol feeding, ERdj5 levels were also markedly increased. Hepatic Dnajc10 correlated with Xbp1s mRNA. Tunicamycin, an ER stress inducer, increased ERdj5 levels. Dnajc10 knockout mice exhibited exacerbated alcohol-induced liver injury and hepatic steatosis. However, the macrophage numbers and chemokine levels were similar to those in wild-type mice. Depletion of Dnajc10 promoted oxidative stress. Ethanol feeding increased hepatic H2O2 levels, and these were further increased in Dnajc10 knockout mice. Additionally, Dnajc10-deficient hepatocytes produced large amounts of reactive oxygen species. Notably, Nrf2, a central regulator of oxidative stress, was decreased by depletion of Dnajc10 in the nuclear fraction of ethanol-treated mouse liver. Consistently, liver tissues from ethanol-fed Dnajc10 knockout mice had reduced expression of downstream antioxidant genes. Furthermore, hepatic glutathione content in the liver of knockout mice declined compared to wild-type mice. In conclusion, our results demonstrate that ethanol-induced ERdj5 may regulate the Nrf2 pathway and glutathione contents, and have protective effects on liver damage and alcohol-mediated oxidative stress in mice. These suggest that ERdj5 has the potential to protect against alcoholic liver disease.

Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism.

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.

Deciphering the key factors determining spatio-temporal heterogeneity of cyanobacterial bloom dynamics in the Nakdong River with consecutive large weirs.

Following the construction of eight large weirs in a 200-km section of the Nakdong River, which is a major water source for the region, harmful cyanobacterial blooms have been occurring annually, causing severe problems with water quality. The present study investigated the community structure of harmful cyanobacteria and identified temporal and spatial patterns in harmful cyanobacterial blooms and their dynamic relationships with physicochemical, hydrological, and meteorological variables in the eight weir sections for 6 years from 2013 to 2018. The dominant harmful cyanobacteria in the eight weir sections were Aphanizomenon and Microcystis spp. There was a successional phenomenon wherein Aphanizomenon spp. first bloomed in spring, and then Microcystis spp. bloomed as water temperatures increased. Additionally, the initiation and duration of the blooms of both genera were affected by the timing and volume of heavy rainfall that caused flushing of cyanobacterial biomass, resulting in direct reduction of cyanobacterial growth in all sections. The harmful cyanobacteria of upstream weirs did not affect the biomass of downstream weirs in terms of either growth initiation or time taken to reach peak biomass, despite being physically connected. Owing to the long retention time during the dry season, similar to what occurs in separate reservoirs, the water quality of each weir section, particularly regarding nutrient characteristics and retention time, were the major factors determining the harmful cyanobacterial abundance, resulting in heterogeneous spatial distribution of harmful cyanobacterial blooms in the Nakdong River.