bims-faldev 2024-05-12 papers

bims-faldev

Biomed News

on Fatty liver disease and extracellular vesicles

Issue of 2024–05–12
eight papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas

Crosstalk in extrahepatic and hepatic system in NAFLD/NASH.
Role of FXR in the development of NAFLD and intervention strategies of small molecules.
Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration.
Probabilistic Scatter Plots for visualizing carbohydrate and lipid metabolism states in Non-Alcoholic Fatty Liver Disease.
Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease.
Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.
Biogenesis of extracellular vesicles from the pathogen perspective: Transkingdom strategies for delivering messages.
Serum Vitamin D Level in Overweight Individuals and Its Correlation With the Incidence of Non-alcoholic Fatty Liver Disease.

Liver Int. 2024 May 08.

Crosstalk in extrahepatic and hepatic system in NAFLD/NASH.

Yiliang Duan, Yan Yang, Shuqiang Zhao, Yuesong Bai, Wenbing Yao, Xiangdong Gao, Jun Yin.

  Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease globally. Non-alcoholic steatohepatitis (NASH) represents an extremely progressive form of NAFLD, which, without timely intervention, may progress to cirrhosis or hepatocellular carcinoma. Presently, a definitive comprehension of the pathogenesis of NAFLD/NASH eludes us, and pharmacological interventions targeting NASH specifically remain constrained. The aetiology of NAFLD encompasses a myriad of external factors including environmental influences, dietary habits and gender disparities. More significantly, inter-organ and cellular interactions within the human body play a role in the development or regression of the disease. In this review, we categorize the influences affecting NAFLD both intra- and extrahepatically, elaborating meticulously on the mechanisms governing the onset and progression of NAFLD/NASH. This exploration delves into progress in aetiology and promising therapeutic targets. As a metabolic disorder, the development of NAFLD involves complexities related to nutrient metabolism, liver-gut axis interactions and insulin resistance, among other regulatory functions of extraneous organs. It further encompasses intra-hepatic interactions among hepatic cells, Kupffer cells (KCs) and hepatic stellate cells (HSCs). A comprehensive understanding of the pathogenesis of NAFLD/NASH from a macroscopic standpoint is instrumental in the formulation of future therapies for NASH.

Keywords:  NAFLD; NASH; adipose tissue; crosstalk; hepatocyte; macrophage

DOI:  https://doi.org/10.1111/liv.15967
Arch Biochem Biophys. 2024 May 03. pii: S0003-9861(24)00143-7. [Epub ahead of print]757 110024

Role of FXR in the development of NAFLD and intervention strategies of small molecules.

Jiachan Long, Yuanhang Xu, Xuerong Zhang, Bingxing Wu, Caiyan Wang.

  Non-alcoholic fatty liver disease (NAFLD) remains a prevailing etiological agent behind hepatocyte diseases like chronic liver disease. The spectrum of processes involved in NAFLD stages includes hepatic steatosis, non-alcoholic fatty liver, and non-alcoholic steatohepatitis (NASH). Without intervention, the progression of NASH can further deteriorate into cirrhosis and ultimately, hepatocellular carcinoma. The cardinal features that characterize NAFLD are insulin resistance, lipogenesis, oxidative stress and inflammation, extracellular matrix deposition and fibrosis. Due to its complex pathogenesis, existing pharmaceutical agents fail to take a curative or ameliorative effect on NAFLD. Consequently, it is imperative to identify novel therapeutic targets and strategies for NAFLD, ideally to improve the aforementioned key features in patients. As an enterohepatic regulator of bile acid homeostasis, lipid metabolism, and inflammation, FarnesoidX receptor (FXR) is an important pharmacological target for the treatment of NAFLD. Manipulating FXR to regulate lipid metabolic signaling pathways is a potential mechanism to mitigate NAFLD. Therefore, elucidating the modulatory character of FXR in regulating lipid metabolism in NAFLD has the potential to yield groundbreaking perspectives for drug design. This review details recent advances in the regulation of lipid depletion in hepatocytes and investigates the pivotal function of FXR in the progress of NAFLD.

Keywords:  FXR; Gut microbiota; Insulin resistance; Lipid steatosis; Liver fibrosis; NAFLD

DOI:  https://doi.org/10.1016/j.abb.2024.110024
Cells. 2024 Apr 26. pii: 754. [Epub ahead of print]13(9):

Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration.

Sanjay Shahi, Taeyoung Kang, Pamali Fonseka.

  Extracellular vesicles (EVs) are membrane-bound particles released by cells to perform multitudes of biological functions. Owing to their significant implications in diseases, the pathophysiological role of EVs continues to be extensively studied, leading research to neglect the need to explore their role in normal physiology. Despite this, many identified physiological functions of EVs, including, but not limited to, tissue repair, early development and aging, are attributed to their modulatory role in various signaling pathways via intercellular communication. EVs are widely perceived as a potential therapeutic strategy for better prognosis, primarily through utilization as a mode of delivery vehicle. Moreover, disease-associated EVs serve as candidates for the targeted inhibition by pharmacological or genetic means. However, these attempts are often accompanied by major challenges, such as off-target effects, which may result in adverse phenotypes. This renders the clinical efficacy of EVs elusive, indicating that further understanding of the specific role of EVs in physiology may enhance their utility. This review highlights the essential role of EVs in maintaining cellular homeostasis under different physiological settings, and also discusses the various aspects that may potentially hinder the robust utility of EV-based therapeutics.

Keywords:  delivery vehicles; exosomes; extracellular vesicles; normal physiology; pathophysiology; therapeutic target

DOI:  https://doi.org/10.3390/cells13090754
Clin Res Hepatol Gastroenterol. 2024 May 03. pii: S2210-7401(24)00086-X. [Epub ahead of print]48(6): 102365

Probabilistic Scatter Plots for visualizing carbohydrate and lipid metabolism states in Non-Alcoholic Fatty Liver Disease.

Jialin Zhou, Tengxiao Liang, Fangliang Xing, Xinyuan Li.

   BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by dysregulated carbohydrate and lipid metabolism, which are its primary features. However, traditional biochemical markers pose challenges for accurate quantification and visualization of metabolic states. This study introduces a novel states-based approach for accurate NAFLD assessment.
METHODS: Joint probabilistic distributions of triglycerides and glycemia were constructed using dual-indicator Probabilistic Scatter Plots based on clinical data (healthy controls: n = 1978; NAFLD patients: n = 471). Patterns of metabolic dysregulation were revealed through comparison against healthy profiles. Self-organizing feature mapping (SOFM) clustered the distributions into four dominant states.
RESULTS: Healthy scatter plots demonstrated a distinct progression of sub-states ranging from very healthy to sub-healthy. In contrast, NAFLD plots exhibited shifted probability centers and outward divergence. SOFM clustering classified the states into: mild; moderate and severe lipid metabolism disorders; and carbohydrate metabolism disorders.
CONCLUSIONS: Probabilistic Scatter Plots, when combined with SOFM clustering, facilitate a states-based quantification of NAFLD metabolic dysregulation. This method integrates multi-dimensional biochemical indicators and their distributions into a cohesive framework, enabling precise and intuitive visualization for personalized diagnosis and monitoring of prognostic developments.

Keywords:  Carbohydrate and lipid metabolism states; NAFLD; Probabilistic Scatter Plots; SOFM clustering

DOI:  https://doi.org/10.1016/j.clinre.2024.102365
Protein Pept Lett. 2024 May 07.

Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease.

Mohammadjavad Sotoudeheian.

  Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a chronic liver disease characterized by the accumulation of fat in the liver and hepatic steatosis, which can progress to critical conditions, including Metabolic dysfunction-associated Steatohepatitis (MASH), liver fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Galectin-3, a member of the galectin family of proteins, has been involved in cascades that are responsible for the pathogenesis and progression of liver fibrosis in MAFLD. This review summarizes the present understanding of the role of galectin-3 in the severity of MAFLD and its associated liver fibrosis. The article assesses the underlying role of galectin-3-mediated fibrogenesis, including the triggering of hepatic stellate cells, the regulation of extracellular degradation, and the modulation of immune reactions and responses. It also highlights the assessments of the potential diagnostic and therapeutic implications of galectin-3 in liver fibrosis during MAFLD. Overall, this review provides insights into the multifaceted interaction between galectin-3 and liver fibrosis in MAFLD, which could lead to the development of novel strategies for diagnosis and treatment of this prevalent liver disease.

Keywords:  Galactose-Binding Lectin; Hepatic Cirrhosis; Liver Fibrosis; Liver Steatosis; Non-alcoholic Fatty Liver Disease; beta-D-Galactosyl-Specific Lectin

DOI:  https://doi.org/10.2174/0109298665301698240404061300
Hepatol Commun. 2024 Jun 01. pii: e0423. [Epub ahead of print]8(6):

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

Zobair M Younossi, Kamal Kant Mangla, Tina Landsvig Berentzen, Katrine Grau, Mette Skalshøi Kjær, Steen Ladelund, Louise Maymann Nitze, Crystal Coolbaugh, Chih-Yuan Hsu, Hannes Hagström.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort.
METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery.
RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage.
CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

DOI: https://doi.org/10.1097/HC9.0000000000000423
Curr Opin Cell Biol. 2024 May 04. pii: S0955-0674(24)00045-0. [Epub ahead of print]88 102366

Biogenesis of extracellular vesicles from the pathogen perspective: Transkingdom strategies for delivering messages.

Alicia Rojas, Neta Regev-Rudzki.

EVs are nanoparticles enclosing proteins, nucleic acids and lipids released by cells and are essential for their metabolism and useful for intercellular communication. The importance of EVs has been highlighted by their use as biomarkers or as vaccine antigens. The release of vesicles is exploited by a wide range of organisms: from unicellular bacteria or protozoa to multicellular prokaryotes like fungi, helminths and arthropods. The mechanisms elucidated to date in each biological group are presented, as well as a discussion of interesting directions for future EV studies.

DOI: https://doi.org/10.1016/j.ceb.2024.102366
Physiol Res. 2024 Apr 30. 73(2): 265-271

Serum Vitamin D Level in Overweight Individuals and Its Correlation With the Incidence of Non-alcoholic Fatty Liver Disease.

Y-L Qu, Y-H Song, R-R Sun, Y-J Ma, Y Zhang.

In this study, we investigated the serum vitamin D level in overweight individuals and its correlation with the incidence of nonalcoholic fatty liver disease (NAFLD). Between May 2020 and May 2021, the Department of Gastroenterology at the People's Hospital of Henan University of Traditional Chinese Medicine treated a total of 321 outpatients and inpatients with NAFLD, who were included in the NAFLD group, while 245 healthy age- and gender-matched individuals were included in the control group. All the data were collected for the relevant indices, including fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine transaminase, and 25-hydroxy vitamin D (25[OH]D. The patients with NAFLD were divided into the normal BMI group, the overweight group, and the obese group, according to the body mass index, and the 25(OH)D levels were compared between the different groups. Spearman's correlation analysis was performed to analyze the correlation between the serum 25(OH)D level and NAFLD. Regarding the serum 25 (OH)D level, it was lower in the NAFLD group than in the control group ([18.36 + 1.41] µg/L vs [22.33 + 2.59] µg/L, t = ?5.15, P<0.001), and was lower in the overweight group than in the normal group ([18.09 ± 5.81] µg/L vs [20.60 ± 4.16] µg/L, t = 0.26, P = 0.041). The serum 25(OH)D level was thus negatively correlated with the incidence of NAFLD in overweight individuals (r = 0.625, P<0.05). In conclusion, the level of 25(OH)D decreased in patients with NAFLD with increasing BMI (normal, overweight, obese). Keywords: Nonalcoholic fatty liver disease, Vitamin D.