Copper plays an important role in many metabolic activities in the human body. Copper level in the human body is in a state of dynamic equilibrium. Recent research on copper metabolism has revealed that copper dyshomeostasis can cause cell damage and induce or aggravate some diseases by affecting oxidative stress, proteasome, cuprotosis, and angiogenesis. The liver plays a central role in copper metabolism in the human body. Research conducted in recent years has unraveled the relationship between copper homeostasis and liver diseases. In this paper, we review the available evidence of the mechanism by which copper dyshomeostasis promotes cell damage and the development of liver diseases, and identify the future research priorities.
Humans ; Copper/metabolism* ; Homeostasis ; Oxidative Stress ; Liver Diseases

Objective To study the effect and mechanism of blueberry on regulating the mitochondrial inner membrane protein mitofilin/Mic60 in an in vitro model of metabolic dysfunction-associated liver disease (MAFLD). Methods L02 human hepatocytes were induced by free fatty acids (FFA) to establish MAFLD cell model. A normal group, a model group, an 80 μg/mL blueberry treatment group, a Mic60 short hairpin RNA (Mic60 shRNA) transfection group, and Mic60 knockdown combined with an 80 μg/mL blueberry treatment group were established. The intracellular lipid deposition was observed by oil red O staining, and the effect of different concentrations of blueberry pulp on the survival rate of L02 cells treated with FFA was measured by MTT assay. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) contents were measured by visible spectrophotometry. The expression of reactive oxygen species (ROS) in hepatocytes was observed by fluorescence microscopy, and the mRNA and protein expression of Mic60 were detected by real-time quantitative PCR and Western blot analysis, respectively. Results After 24 hours of FFA stimulation, a large number of red lipid droplets in the cytoplasm of L02 cells was observed, and the survival rate of L02 cells treated with 80 μg/mL blueberry was higher. The results of ALT, AST, TG, TC, MDA and the fluorescence intensity of ROS in blueberry treated group were lower than those in model group, while the levels of SOD, GSH, Mic60 mRNA and protein in blueberry treated group were higher than those in model group. Conclusion Blueberry promotes the expression of Mic60, increases the levels of SOD and GSH in hepatocytes, and reduces the production of ROS, thus alleviating the injury of MAFLD hepatocytes and regulating the disorder of lipid metabolism.
Humans ; Blueberry Plants/chemistry* ; Hepatocytes/metabolism* ; Liver/metabolism* ; Liver Diseases/metabolism* ; Reactive Oxygen Species/metabolism* ; Superoxide Dismutase/metabolism* ; Superoxides/metabolism* ; Mitochondrial Membranes/metabolism* ; Mitochondrial Proteins/metabolism* ; Plant Extracts/pharmacology*

The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver's cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.
Humans ; Liver/surgery* ; Hepatocytes/transplantation* ; Stem Cells/metabolism* ; Liver Diseases/surgery*

Autophagy is one of several hepatic metabolic processes in which starved cells are supplied with glucose, free fatty acids, and amino acids to produce energy and synthesize new macromolecules. Moreover, it regulates the quantity and quality of mitochondria and other organelles. As the liver is a vital metabolic organ, specific forms of autophagy are necessary for maintaining liver homeostasis. Protein, fat, and sugar are the three primary nutrients that can be altered by different metabolic liver diseases. Drugs that have an effect on autophagy can either promote or inhibit autophagy, and as a result, it can either increase or inhibit the three major nutritional metabolisms that are affected by liver disease. Thus, this opens up a novel therapeutic option for liver disease.
Humans ; Liver/metabolism* ; Liver Diseases ; Autophagy ; Metabolic Diseases ; Mitochondria

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.
Humans ; Orphan Nuclear Receptors/metabolism* ; Receptors, Steroid/physiology* ; Ligands ; Liver ; Liver Diseases ; Intercellular Signaling Peptides and Proteins

Mitochondrial DNA is the mitochondria's own genetic material located within the mitochondrial matrix and is involved in cellular metabolism and energy supply. Mitochondrial DNA damage exacerbates oxidative stress by increasing the release of reactive oxygen species, while mitochondrial DNA release also triggers apoptosis and activates immune inflammatory responses through damage-related molecular patterns. Mitochondrial autophagy regulates mitochondrial DNA damage and release through a negative feedback mechanism to maintain intracellular homeostasis. Recent studies have shown that the occurrence and development of chronic liver disease are closely related to mitochondrial DNA-mediated immune inflammatory responses and oxidative stress.
Apoptosis ; Autophagy ; DNA, Mitochondrial/metabolism* ; Humans ; Liver Diseases ; Mitochondria ; Oxidative Stress ; Reactive Oxygen Species/metabolism*

Lipophagy is a kind of selective autophagy, which can selectively identify and degrade lipid droplets and plays an important role in regulating cellular lipid metabolism and maintaining intracellular lipid homeostasis. Exercise can induce lipophagy and it is also an effective means of reducing body fat. In this review, we summarized the relationship between exercise and lipophagy in the liver, pancreas, adipose tissue, and the possible molecular mechanisms to provide a new clue for the prevention and treatment of fatty liver, obesity and other related metabolic diseases by exercise.
Autophagy/physiology* ; Humans ; Lipid Droplets/metabolism* ; Lipid Metabolism/physiology* ; Liver ; Metabolic Diseases/metabolism*

The present study investigated the effect of extract of Poria cocos polysaccharides(PCP) on cytochrome P450 2 E1(CYP2 E1) and nuclear factor κB(NF-κB) inflammatory signaling pathways in alcoholic liver disease(ALD) mice and explored its protective effect and mechanism. Sixty male C57 BL/6 N mice of SPF grade were randomly divided into a control group, a model group, a positive drug group(bifendate, 200 mg·kg~(-1)), and high-(200 mg·kg~(-1)) and low-dose(50 mg·kg~(-1)) PCP groups. Gao-binge mo-del was induced and the mice in each group were treated correspondingly. Liver morphological and pathological changes were observed and organ index was calculated. Serum levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were detected. Malondialdehyde(MDA) and superoxide dismutase(SOD) in liver tissues were detected by assay kits. The levels of interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) were detected by ELISA. The activation of macrophages was observed by immunofluorescence staining and protein expression of CYP2 E1, Toll-like receptor 4(TLR4), NF-κB p65, and phosphorylated NF-κB p65(p-NF-κB p65) were analyzed by Western blot. The ALD model was properly induced. Compared with the model group, the PCP groups significantly improved the pathological injury of liver tissues. Immunofluorescence staining revealed that compared with the model group, the groups with drug intervention showed decreased macrophages in liver tissues. Additionally, the PCP groups showed reduced ALT, AST, MDA, IL-6, and TNF-α(P<0.05), and potentiated activity of SOD(P<0.01). PCP extract has the protective effect against alcoholic liver injury in mice, and the underlying mechanism may be related to the regulation of the expression of CYP2 E1 and inhibition of TLR4/NF-κB inflammatory signaling pathway to reduce oxidative stress and inflammatory injury, thereby inhibiting the development of ALD.
Animals ; Cytochrome P-450 CYP2E1/pharmacology* ; Liver ; Liver Diseases, Alcoholic/pathology* ; Male ; Mice ; NF-kappa B/metabolism* ; Plant Extracts/pharmacology* ; Polysaccharides/pharmacology* ; Wolfiporia

Objective: To explore abdominal fat mass distribution and contents among obese children via magnetic resonance imaging (MRI), and analyze the correlations of abdominal adipose tissue with anthropometric and metabolic parameters. Methods: Cross-sectional study. There were 60 obese children admitted to the Children's Health Care Department and Endocrinology Department at Children's Hospital of Nanjing Medical University from July 2016 to December 2018. Children's gender, age, height, weight, body composition, waist circumference and blood pressure were recorded. The levels of fasting blood glucose, lipids, insulin were measured, and liver ultrasound was performed, and the body mass index Z score (BMI-Z), waist-to-height ratio (WHtR) and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. In addition, contents of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and total abdominal adipose tissue (TAAT) were calculated according to feedback of abdominal MRI scan images. The associations between the contents of abdominal adipose tissue, physical examination status and metabolic disorders among obese children were analyzed through correlation analysis and regression analysis. Receiver operating characteristic (ROC) curve was used to compare the accuracy of fat mass in different parts of the abdomen in predicting their metabolic disorders. Results: A total of 60 children were enrolled in the study, included 44 boys and 16 girls, with age of (9.2±1.4) years. The contents of SAT, VAT and TAAT among the 60 children were positively associated with BMI-Z (r=0.60, 0.46, 0.59), body fat percentage (r=0.64, 0.67, 0.68) and waist-to-height ratio (r=0.60, 0.57, 0.61) (all P<0.01). Meanwhile, contents of SAT and TAAT were also positively correlated with systolic blood pressure (r=0.47, 0.49), triglyceride (r=0.33, 0.35) and HOMA-IR (r=0.33, 0.28)(all P<0.05). In order to adjust the confounding effects among various variables, regression analysis was applied and the result showed that the body fat percentage (β=0.59, 0.66, 0.65) and waist-to-height ratio (β=0.53, 0.63, 0.59) were most related to abdominal fat contents (all P<0.01), including SAT, VAT and TAAT among obese children. According to ROC, SAT had outstanding evaluation performances for the diagnosis of insulin resistance and metabolic syndrome, while VAT had excellent evaluation performances for non-alcoholic fatty liver disease (area under curve=0.68, 0.69, 0.69, 95%CI 0.54-0.82, 0.55-0.84, 0.53-0.85, P=0.017, 0.014, 0.019). Conclusions: As one of the best indexes, body fat percentage and WHtR can be used to predict the contents of SAT, VAT and TAAT among obese children. With the increase of abdominal SAT or VAT, the risks for insulin resistance, metabolic syndrome and non-alcoholic fatty liver disease would increase. Assessment of abdominal fat and metabolic risks in obese children should combine BMI-Z with waist circumference and body composition analysis.
Abdominal Fat/metabolism* ; Body Mass Index ; Child ; Cross-Sectional Studies ; Female ; Humans ; Insulin Resistance ; Magnetic Resonance Imaging ; Male ; Metabolic Diseases/metabolism* ; Metabolic Syndrome/metabolism* ; Non-alcoholic Fatty Liver Disease ; Pediatric Obesity/metabolism*

Objective: To study the protective effects of Lycium ruthenicum Murr. juice on alcoholic liver injury in rats and explore the regulatory mechanism of toll-like receptors 4 (TLR4)/p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway in this process. Methods: Sixty male SD rats were randomly divided into control group (C), model group (M), low-dose Lycium ruthenicum Murr. juice group (LLM), medium-dose Lycium ruthenicum Murr. juice group (MLM) and high-dose Lycium ruthenicum Murr. juice group (HLM), 12 rats in each group. The group M, LLM, MLM and HLM were treated with 20 ml/kg (8 g/(kg·d)) ethanol (400 g/L) intragastrically and the gavage was divided into two sessions, group C was treated with an equal volume of distilled water at the same time point. Four hours before the first alcohol gavage session, rats in each dose group of Lycium ruthenicum Murr. juice were administered with 2.4, 4.8, 9.6 ml/(kg·d) Lycium ruthenicum Murr. juice respectively, and the other groups were given equal volume of distilled water at the corresponding time points. Four weeks later, the rats were sacrificed 24 hours after the end of the last experiment, blood and liver were collected. The liver index was calculated. The morphology of the liver was observed by HE staining. The expressions of hepatic TLR4, p38 MAPK and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were detected by immunohistochemistry. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by colorimetry. The levels of hepatic tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-10 (IL-10) and interleukin-18 (IL-18) were detected by enzyme linked immunosorbent assay. Results: Compared with group C, the alcoholic liver injury model was established successfully in Group M. Compared with group M, related indicators in each dose group of Lycium ruthenicum Murr. juice were improved, the improvement of hepatic morphology in group HLM was the most significant, the liver index, the levels of serum ALT, AST and hepatic TLR4, p38 MAPK/p-p38 MAPK ratio, TNF-α, IL-1β, IL-18 were decreased (P＜ 0.05 or P＜0.01), while the level of hepatic IL-10 was increased (P＜0.01). Comparison among the dose groups of Lycium ruthenicum Murr. juice, the levels of liver index, serum AST and hepatic TLR4, p38 MAPK/p-p38 MAPK ratio, TNF-α, IL-18 in HLM were lower than those in LLM (P＜0.05 or P＜0.01); the level of hepatic IL-10 in HLM was higher than that in LLM and MLM (P＜0.05 or P＜0.01); the other indicators in each dose group had no statistical difference (P＞0.05). Conclusion: Lycium ruthenicum Murr. juice can improve the inflammatory stress by regulating TLR4/p38 MAPK signaling pathway, relieve alcoholic liver injury in rats, and the effect of high-dose group is better than the others.
Animals ; Fruit and Vegetable Juices ; Interleukin-10 ; Interleukin-18 ; Liver/metabolism* ; Liver Diseases, Alcoholic/therapy* ; Lycium/chemistry* ; Male ; Rats ; Rats, Sprague-Dawley ; Toll-Like Receptor 4 ; Tumor Necrosis Factor-alpha ; p38 Mitogen-Activated Protein Kinases/metabolism*