Chronic Liver Injury Research Articles

Deacetylation of BAP31 by sirtuin 2 attenuates apoptosis of hepatocytes induced by endoplasmic reticulum stress, in chronic alcoholic liver injury.

Endoplasmic reticulum (ER) stress is a crucial pathogenic mechanism in alcoholic liver disease (ALD). B-cell receptor-associated protein 31 (BAP31) can regulate ER homeostasis and anti-apoptosis, but the function and regulation of BAP31 in ALD are unclear. The purpose of this study is to investigate whether BAP31 deacetylation by sirtuin 2 could attenuate ER stress and apoptosis during ALD and to explore whether carnosol could alleviate ALD through the sirtuin 2/BAP31 pathway. A mouse model of ALD was established by feeding mice with alcoholic liquid chow. In vitro, AML-12 cells were stimulated with alcohol. The therapeutic efficacy of carnosol in protecting mice from ALD pathogenesis was evaluated. Treatment with carnosol protected mice against ALD and attenuated hepatocyte ER stress and apoptosis. Carnosol up-regulated sirtuin 2 expression, and sirtuin 2knockdown abolished the protective effect of carnosol during ALD. Moreover, sirtuin 2 knockdown reduced BAP31 expression. Carnosol-mediated BAP31 up-regulation was abolished upon knockdown of sirtuin 2. Mechanistically, sirtuin 2 selectively regulates the deacetylation of BAP31 at K158. Taken together, the present study shows for the first time that carnosol exerts its protective efficacy through facilitating sirtuin 2-mediated deacetylation of BAP31 at K158 to attenuate hepatocyte ER stress and apoptosis during ALD. These results provide new therapeutic targets and approaches for combating chronic ALD.

SURGICAL RISK ASSESSMENT IN PATIENTS WITH LIVER CIRRHOSIS – A LITERATURE REVIEW

Patients with chronic liver injury and liver cirrhosis develop disease-specific pathophysiological abnormalities. These specific findings compromise the functional activity of other organs and systems, leading to poor postoperative outcomes and increased morbidity and mortality rates in this population of patients. This requires a thorough analysis of the aforementioned pathophysiological abnormalities in order to optimize the patient's clinical condition in the preoperative period and to improve their perioperative performance status. The impaired physiological reserves in patients with liver cirrhosis necessitate a detailed assessment of the surgical risk in each specific patient. For this purpose, there are multiple classification and scoring systems for assessment – ​​Child-Pugh – Turcotte (CPT), Model of end-stage liver disease (MELD), Model of end-stage liver disease – Na (MELD – Na), Albumin – Bilirubin score (ALBI), each with specific indications for clinical use. This literature review on the topic examines the pathophysiological changes in patients with liver cirrhosis and the above-mentioned classification systems for risk assessment, as well as the advantages and disadvantages of each of them.

Adverse events of hepatic anti-fibrotic agents in phase 3 and above clinical trials: a descriptive analysis of the WHO-VigiAccess database

IntroductionLiver fibrosis is a pathological condition in response to chronic liver injuries. Currently, there is no Food and Drug Administration (FDA) approved pharmacotherapy for liver fibrosis. Advances in understanding hepatic fibrogenesis have led to the development of anti-fibrotic agents, and some of them have shown promise in phase 3 and above clinical trials. However, adverse drug reactions (ADRs) associated with emerging anti-fibrotic agents may hinder their efficacy and clinical applicability. This study assessed ADRs associated with anti-fibrotic agents as reported in the World Health Organization (WHO) VigiAccess database and compared the adverse reaction characteristics of these agents for optimizing therapeutic strategies.MethodsA detailed search was conducted on ClinicalTrial.gov to identify phase 3 or 4 clinical trials involving hepatic anti-fibrotic agents. The ADR reports were retrieved from the WHO-VigiAccess database, with data categorized by demographic characteristics, geographic distribution, and System Organ Classes (SOCs). The most frequently reported ADRs were identified through descriptive analysis. Disproportionality analysis, measured by reporting odd ratio (ROR) and proportional reporting ratio (PRR), was performed to evaluate ADRs related to gastrointestinal disorders.ResultsFive hepatic anti-fibrotic agents (empagliflozin, liraglutide, candesartan, obeticholic acid, and resmetirom) were identified. A total of 130,567 ADR reports were analyzed, with empagliflozin, liraglutide, and candesartan showing significantly higher ADRs. The most frequently reported SOCs included gastrointestinal disorders (29.44%), general disorders (24.12%), and nervous system disorders (14.42%). Liraglutide demonstrated a higher risk of gastrointestinal ADRs (ROR: 4.629, 95% CI: 4.517–4.744; PRR: 3.566, 95% CI: 3.492–3.642) compared to the other agents. Severe ADRs were reported in empagliflozin, such as ketoacidosis and infections, while liraglutide was associated with pancreatitis and candesartan with acute kidney injury. Serious ADR rates varied, with candesartan reporting the highest proportion (7.28%).ConclusionWhile hepatic anti-fibrotic agents showed promise in addressing liver fibrosis, their ADR profiles underscore the importance of pharmacovigilance and personalized treatment approaches. Future efforts should focus on improving the pharmacovigilance system, expanding population diversity in trials, and conducting ongoing research and extensive post-marketing surveillance.

Analysis of Immunometabolic Profiles in Patients With Chronic Drug-Induced Liver Injury and Validation in Mice to Reveal Potential Mechanisms.

The mechanism underlying chronic drug-induced liver injury (DILI) remains unclear. Immune activation is a common feature of DILI progression and is closely associated with metabolism. We explored the immunometabolic profile of chronic DILI and the potential mechanism of chronic DILI progression. Plasma and peripheral blood mononuclear cells from patients with chronic DILI were analyzed using multiplex immunoassays and untargeted metabolomics to reveal their immunometabolic profile. The effects and potential mechanisms of chronic DILI-related metabolite on acute or chronic liver injury induced by LPS or CCl4 in mice were investigated. Patients with chronic DILI exhibited elevated plasma IL-6, IL-12p70, IL-15 and reduced IL-10 levels. The percentage of IL-12+ monocytes was higher, while that of CD206+ monocytes, IL-10+ monocytes, Th2, Treg, and IL-10+ CD4+ T cells were lower in patients with chronic DILI compared to those with acute DILI. We identified the most significantly increased metabolite in patients with chronic DILI was cis-aconitic acid (CAA). Administration of CAA can attenuate liver injury in mice with acute liver injury induced by LPS or CCl4 and promote the spontaneous resolution of liver fibrosis in mice with chronic live injury induced by CCl4. The protective mechanism of CAA against liver injury is associated with the inhibition of hepatic macrophage infiltration and polarization, which is achieved by inhibiting the secretion of neutrophil-derived IL-33 and subsequent phosphorylation of GATA3. CAA, which is elevated in patients with chronic DILI, protects against liver injury by inhibiting hepatic macrophage infiltration and polarization through the suppression of the IL-33/GATA3 pathway, suggesting that CAA may serve as a potential target for regulating tissue repair in liver injury.

Key role of macrophages in the progression of hepatic fibrosis.

Liver fibrosis is a pathological change characterized by excessive deposition of extracellular matrix caused by chronic liver injury, and the mechanisms underlying its development are associated with endothelial cell injury, inflammatory immune cell activation, and HSC activation. Furthermore, hepatic macrophages exhibit remarkable heterogeneity and hold central functions in the evolution of liver fibrosis, with different subgroups exerting dual effects of promotion and regression. Currently, targeted macrophage therapy for reversing hepatic fibrosis has been extensively studied and has shown promising prospects. In this review, we will discuss the dual role of macrophages in liver fibrosis and provide new insights into reversing liver fibrosis based on macrophages.

In vivo transplantation of intrahepatic cholangiocyte organoids with decellularized liver-derived hydrogels supports hepatic cellular proliferation and differentiation in chronic liver injury.

The limited replicative potential of primary hepatocytes (Hep) is a major hurdle for obtaining sufficient quantity and quality hepatocytes during cell therapy in patients with liver failure. Intrahepatic cholangiocyte organoids (ICOs) derived from intrahepatic bile ducts differentiate into both hepatocytes and cholangiocytes in vitro. Here, we studied in vivo effects of transplanting ICOs and Hep in chronic liver injury mice models. Well characterized primary mouse ICOs and Hep were mixed in decellularized liver (DCL) matrix hydrogels and injected into the subcapsular left lateral liver lobe of CCl4-induced liver injury models whereas mice given DCL alone were in the sham group. Two weeks post-transplantation, transplanted liver lobes were collected and studied by histology and RNA sequencing. Transplanted animals did not exhibit any tumors, mortality or morbidity. Mice livers transplanted with ICOs had increased cellular proliferation and vascularization as compared to Hep transplanted mice or sham. Collagen deposition in the liver was significantly reduced and serum albumin levels were significantly increased in transplanted groups compared to the sham group. Expression of genes associated with hepatocyte differentiation was highest in Hep transplanted livers among the three groups, but they were also upregulated in ICO transplanted livers compared to sham. Our study demonstrates that ICOs encapsulated in DCL hydrogels when transplanted in chronically injured mice livers engraft well and show hepatocyte differentiation and reduction of fibrosis, indicating that hydrogel transplanted cholangiocyte organoids may serve as an efficient cell source and therapy for renewal of hepatocytes, restoration of hepatocyte functions and resolution of liver injury.

Corrigendum to “Protective effects of Longhu Rendan on chronic liver injury and fibrosis in mice” [Liver Res. 6 (2022) 93–102

Corrigendum to “Protective effects of Longhu Rendan on chronic liver injury and fibrosis in mice” [Liver Res. 6 (2022) 93–102

Treatment of Liver Fibrosis with Chinese Medicines and Extracts: A Review

Hepatic fibrosis (HF), a global issue that develops gradually during the repeated repair process of chronic liver injury caused by various factors, can progress to irreversible cirrhosis and hepatocellular carcinoma. Currently, there are no approved chemical or biological drugs for the treatment of liver fibrosis. Modern medicine primarily focuses on addressing the underlying causes of liver fibrosis. HF is classified as an accumulative disease in the Yellow Emperor's Internal Classic, which is the earliest and most influential extant medical classic in China. Thousands of years of treatment experience have accumulated a large number of effective Chinese medicines. In recent years, studies on the anti-liver fibrosis effects of Chinese medicine have mainly focused on the curative effects of extracts and compounds. Studies have shown that the treatment and prevention of liver fibrosis through Chinese medicine demonstrate a comprehensive pharmacological effect that involves multiple pathways and targets. Therefore, further in-depth research in this field is both promising and necessary. However, it is crucial to expand clinical application studies, as the current research on the anti-liver fibrosis effects of TCM is predominantly limited to laboratory investigations. In this review, we summarized the pharmacological effects, targets and related mechanisms of 13 traditional Chinese medicines in the treatment of HF in the past five years, in order to provide comprehensive information for the development of anti-liver fibrosis drugs.

Therapeutic Potential of Hongjam in A Diethylnitrosamine and Thioacetamide-induced Hepatocellular Carcinoma Mouse Model.

Hepatocellular carcinoma (HCC) is the most common and lethal type of primary liver cancer, frequently arising from chronic liver injury and inflammation. Despite treatment advancements, HCC prognosis remains poor, emphasizing the need for effective preventive and therapeutic strategies. This study investigates the hepatoprotective and anti-tumor effects of Hongjam, a steamed freeze-dried silkworm powder, in a diethylnitrosamine (DEN) and thioacetamide (TAA)-induced HCC mouse model. Mice were administered DEN intraperitoneally for 8 weeks, followed by TAA in drinking water for 9 weeks, with Hongjam supplementation (0.01, 0.1, and 1 g/kg) provided daily through food. Hongjam markedly reduced the tumor incidence, the size, and the histological lesions compared to the DEN/TAA group. Serum biochemical analysis revealed reduction in liver damage markers, including alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin, with a notable decrease in total bilirubin surpassing. Immunohistochemical and Western blot analyses demonstrated that Hongjam downregulated expression of proliferation markers, including Ki67, phosphorylation of protein kinase B, and proliferating cell nuclear antigen, while upregulating the pro-apoptotic protein Bcl-2-associated X protein, indicating its dual role in suppressing proliferation and promoting apoptosis. Furthermore, Hongjam inhibited angiogenesis by suppressing the expression of key markers, including interleukin 6, VEGF, hypoxia-inducible factor-1 subunit alpha, platelet-derived growth factor subunit beta, matrix metalloproteinase-2, and cluster of differentiation 31, thereby disrupting the tumor microenvironment. These findings suggest that Hongjam exerts multifaceted protective effects against HCC by targeting proliferation, apoptosis, and angiogenesis pathways, while also mitigating liver damage. This study highlights the potential of Hongjam as a functional food or a complementary therapeutic agent for HCC prevention and management.

Coleus vettiveroides Root Extract Protects Against Thioacetamide-Induced Chronic Liver Injury by Inhibiting NF-κB Signaling Pathway.

The roots of Coleus vettiveroides (CV) have been traditionally used in Indian medicinal systems such as Ayurveda and Siddha for its antioxidant, anti-inflammatory, and antidiabetic effects. This study examines the antifibrotic potential of CV ethanolic root extract (CVERE) against thioacetamide (TAA)-induced liver fibrosis in Wistar rats. TAA was administered via i.p., thrice weekly for 11 weeks to induce liver fibrosis in rats. In separate groups, rats were administered with TAA and were concurrently treated with CVERE 125 mg/kg, CVERE 250 mg/kg, and silymarin (SIL) 100 mg/kg. Liver marker enzymes of hepatotoxicity, oxidative stress markers, proinflammatory marker gene expression (TNF-α, NF-κB, COX, and ILs), fibrotic marker gene expression (collagen I and III), immune histochemical expression of fibrosis marker proteins, and histopathologic changes were analyzed. TAA administration led to a significant (p < 0.001) increase in the serum level of hepatotoxic marker enzymes. The TAA-treated group showed higher levels (p < 0.001) of MDA and reduced activities of SOD and CAT in the liver. TAA administration increased CYP2E1 expression, proinflammatory, and fibrotic marker gene expressions in rat liver. The histopathology of the liver confirms TAA-induced architectural distortion and fibrotic changes. CVERE and SIL simultaneous treatments significantly protected against TAA-induced oxidative stress, inflammation, and liver fibrosis. In conclusion, CVERE inhibited TAA-induced liver fibrosis through downregulation of TAA metabolic activation, redox imbalance, and inflammation through repression of the NF-κB pathway.

Lhx2 specifically expressed in HSCs promotes liver regeneration and inhibits liver fibrosis.

Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with HSCs being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms. Through comparing acute and chronic liver injury mouse models induced by CCl 4 injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and profibrogenic genes following injury. Analyzing RNA-seq data from primary HSCs of these models, along with publicly available single-cell RNA-seq data of HSCs, we identified transcription factor Lhx2, specifically expressed in HSCs, as a potential regulator of the dual functions. Notably, Lhx2 showed significantly higher expression in HSCs from healthy liver tissue compared to fibrotic liver, in both mouse and human models. Lhx2 knockdown impaired liver function recovery and cellular proliferation after acute liver injury. Consistent changes were observed in mice with HSC-specific Lhx2 overexpression. In addition, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an antifibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation, and migration, and upregulated SMAD6 to block the TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration. We demonstrated that Lhx2 had pro-regenerative and antifibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases.

Practical Recommendations for the Diagnosis and Management of Lysosomal Acid Lipase Deficiency with a Focus on Wolman Disease.

Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease with two distinct phenotypes, an infantile-onset form (formerly Wolman disease) and a later-onset form (formerly cholesteryl ester storage disease). The objective of this narrative review is to examine the most important aspects of the diagnosis and treatment of LAL-D and to provide practical expert recommendations. The infantile-onset form occurs in the first weeks of life and is characterized by malnourishment and failure to thrive due to gastrointestinal impairment (vomiting, diarrhea, malabsorption), as well as systemic inflammation, hepatosplenomegaly, and adrenal calcifications. Mortality is close to 100% before one year of life in the absence of specific treatment. The later-onset form can be diagnosed in childhood or adulthood and is characterized by chronic liver injury and/or lipid profile alterations. When LAL-D is suspected, enzyme activity should be determined to confirm the diagnosis, with analysis from a dried blood spot sample being the quickest and most reliable method. In infantile-onset LAL-D, the initiation of enzyme replacement therapy (sebelipase α) and careful nutritional management with a low-lipid diet is very urgent, as prognosis is directly linked to the early initiation of specific treatment. In recent years, our knowledge of the management of LAL-D has increased considerably, with improvements regarding the initial enzyme replacement therapy dose and careful nutritional treatment with a low-lipid diet to decrease lipid deposition and systemic inflammation, leading to better outcomes. In this narrative review we offer a quick guide for the initial management of infantile-onset LAL-D.

Autologous Bone Marrow-Derived Mesenchymal Stem Cell Transplantation for Decompensated Post-Hepatitis B Cirrhosis: A Case Report

End-stage liver disease (ESLD) represents the terminal phase of chronic liver injury, characterized by overt clinical manifestations and severe complications that significantly impair the quality of life. The condition often culminates in a variety of symptoms, including jaundice, ascites, and hepatic encephalopathy, which reflect the liver&amp;apos;s inability to perform its essential functions. Liver transplantation remains the definitive treatment for ESLD; however, limitations in donor organ availability necessitate exploration of alternative therapeutic strategies. we present a case of a 71-year-old Asian male with decompensated post-hepatitis B cirrhosis, who had a one-year history of hematemesis and melena. Endoscopic evaluation confirmed the presence of esophageal-gastric varices, further corroborating portal hypertension and hypersplenism. This patient underwent treatment with autologous bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation. Following the procedure, the patient demonstrated significant clinical improvement, suggesting the safety and potential feasibility of BM-MSC transplantation for patients with ESLD. The field of BM-MSC transplantation has witnessed significant progress in recent years, emerging as a promising therapeutic approach for ESLD. This innovative treatment modality harnesses the regenerative capabilities of stem cells to promote liver repair and function. Notably, BM-MSCs possess immunomodulatory properties that may mitigate inflammation and fibrosis in the liver, thereby addressing some of the underlying pathophysiology associated with ESLD. This case presentation highlights the potential application of BM-MSC therapy in patients with decompensated cirrhosis. The findings underscore the need for further research and refinement of clinical application techniques to fully realize the broad therapeutic possibilities of BM-MSC transplantation for ESLD. As we advance our understanding of stem cell therapies, it is crucial to conduct larger studies to evaluate long-term outcomes and establish standardized protocols for treatment.

Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.

Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.

Ampelopsis grossedentata tea alleviating liver fibrosis in BDL-induced mice via gut microbiota and metabolite modulation

Liver fibrosis (LF) is a common sequela to diverse chronic liver injuries, leading to rising rates of cirrhosis and hepatocellular carcinoma (HCC). As the medicinal and edible homologous material, traditional teas have exhibited promising applications in the clinical management of liver fibrosis. Here, we generated a liver fibrosis mouse model to explore the potent therapeutic ability of Ampelopsis grossedentata (AG) tea on this condition by multi-omics analysis. The biochemistry results pointed towards mitigated increases of ALT, AST, TBIL, and ALP triggered by BDL in the AG-treated group. Examination using H&E and Sirius Red staining revealed severe liver injuries, inflammation infiltration, amplified fibrosed regions, and the creation of bile ducts, all of which were fallout from BDL. Immunohistochemistry findings also implicated a noteworthy upregulation of the HSC activation marker α-smooth muscle actin (α-SMA) and the fibrosis marker collagen I in the BDL group. However, these symptoms demonstrated a significant improvement in the group treated with 100 mg/kg AG. Findings from the Western Blot test corroborated the prominent elevation of TNF-α, col1a1, α-SMA, and TGF-β, instigated by BDL, while AG treatment meaningfully modulated these proteins. Furthermore, our study underscored the potential involvement of several microbiota, such as Ruminococcaceae UCG-014, Eubacterium Ruminantium, Ruminococcus 1, Christensenellaceae R-7, Acetatifactor, Dubosiella, Parasutterella, Faecalibaculum, and Defluviitaleaceae UCG-011, in the progression of liver fibrosis and the therapeutic efficacy of AG. This investigation shows that during the process of AG ameliorating BDL-induced liver fibrosis, bile acid derivatives such as CDCA, TCDCA, 3-DHC, UCA, DCA, among others, play significant roles. In this study, we identified that several non-bile acid metabolites, such as Deltarasin, Thr-Ile-Arg, etc., are entailed in the process of AG improving liver fibrosis.

Transient receptor potential channel 6 knockout ameliorates hepatic fibrosis by inhibiting the activation and proliferation of hepatic stellate cells.

Hepatic fibrosis is a common outcome of chronic liver injury and can eventually lead to cirrhosis, which is a major public health concern. Hepatic stellate cells (HSCs) are the major producers of extracellular matrix (ECM) and regulate the synthesis and decomposition of ECM, but the specific mechanism of them remains unclear. Transient receptor potential channel 6 (TRPC6), a non-selective cation channel, plays an important role in organic fibrosis. However, the role of TRPC6 in liver fibrosis is rarely studied. Here, we investigated the function of TRPC6 in the activation of the human hepatic stellate cell line LX-2 in vitro and bile duct ligation (BDL)-induced hepatic fibrosis in vivo by western blot, Ca2+ imaging, and immunohistochemistry. We first found that TRPC6 was upregulated in fibrotic liver tissues and TRPC6 knockout inhibited BDL-induced hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) treatment increased TRPC6 expression and thapsigargin (Tg)-mediated SOCE in LX-2 cells, which was decreased by the TRPC6 specific inhibitor SAR7334. Blockage of TRPC6 by SAR7334 or TRPC6-shRNA transfection attenuated TGF-β1-induced LX-2 cell activation and proliferation via the PI3K/AKT/p70S6K signaling pathway. These observations suggested that TRPC6 contribute to LX-2 cell activation and hepatic fibrosis, and downregulation of TRPC6 may become a therapeutic strategy for the treatment of hepatic fibrosis in the future.

Stem cell exosomes: new hope and future potential for relieving liver fibrosis.

Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.

Pea Albumin Alleviates Oleic Acid-Induced Lipid Accumulation in LO2 Cells Through Modulating Lipid Metabolism and Fatty Acid Oxidation Pathways.

Excessive lipid accumulation in the liver can cause NAFLD, leading to chronic liver injury. To relieve liver lipid accumulation by dietary proteins, this study used oleic acid (OA) induction to establish a stable in vitro LO2 cell lipid accumulation model. This model was used to explore the mechanism by which pea albumin (PA) regulates lipid levels in LO2 cells. PA has been shown to ameliorate OA-induced lipid accumulation in LO2 cells by reducing the aggregation of intracellular lipid droplets and lowering cell TG and TC levels. In addition, it can alleviate OA-induced LO2 cell damage and oxidative stress, reduce cellular ALT and AST secretion, lower cellular MDA levels, and increase GSH-Px viability. Regulation of lipid metabolism in LO2 cells involves inhibiting the cellular lipid synthesis pathway and activating the expression of proteins related to the triglyceride catabolic and fatty acid oxidation pathways. PA contributes to regulating lipid accumulation in LO2 cells. This study provides new insights into alleviating liver fat accumulation and a theoretical basis for exploring the mechanism of protein regulation of liver cell lipid metabolism.

OPN-Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH-Associated Liver Fibrosis.

Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.

Sarcopenia Prevalence in Liver Cirrhosis Patients Using MRI and Handgrip Strength Measurements

Background: Cirrhosis, a leading cause of mortality worldwide, is histologically represented as formation of regenerative nodules encircled by fibrous bands caused by chronic liver injury. Nutritional status in cirrhotic patients is challenging to assess due to fluid accumulation resulting from impaired protein synthesis. Factors such as reduced food intake, malabsorption, and altered macronutrient metabolism negatively impact the nutritional status, leading to sarcopenia. The development of sarcopenia is multifactorial and is linked to lower survival rates. Aim: To assess sarcopenia prevalence in liver cirrhosis patients using MRI and handgrip strength measurements. Discussion: Impaired food intake in liver cirrhosis results from a combination of factors including loss of appetite, hormonal changes, early satiety, ascites, nausea, taste disturbances, and functional dyspepsia. Malabsorption can also occur due to portosystemic shunting, reduced bile production, chronic pancreatitis, and small intestinal bacterial overgrowth, all of which contribute to sarcopenia. It also arises from complex interactions involving impaired glycogen synthesis, inadequate nutrition, disrupted skeletal muscle protein synthesis and underlying hypermetabolism. Conclusion: MRI-based assessments indicate there is a significant occurrence of sarcopenia in individuals with cirrhosis. Our findings reveal that handgrip strength, when correlated with MRI results, is a reliable predictor of sarcopenia in these patients.