bims-faldev Biomed News
on Fatty liver disease and extracellular vesicles
Issue of 2024‒05‒19
twelve papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas
  1. [Clinical status and challenges of new drugs for metabolic dysfunction-associated fatty liver disease].
  2. From NAFLD to NASH: Understanding the spectrum of non-alcoholic liver diseases and their consequences.
  3. Resmetirom, the long-awaited first treatment for metabolic dysfunction-associated steatohepatitis and liver fibrosis?
  4. [Analysis of non-alcoholic fatty liver disease differences from metabolic dysfunction-associated fatty liver disease based on clinical features].
  5. Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.
  6. Protective effects of dopamine against non-alcoholic steatohepatitis via inhibiting p65 pathways in vivo and in vitro.
  7. Evaluation of the Diagnostic Utility of Selected Serum Adipokines and Cytokines in Subjects with MASLD-A Pilot Study.
  8. Bioengineering scalable and drug-responsive in vitro human multicellular non-alcoholic fatty liver disease microtissues encapsulated in the liver extracellular matrix-derived hydrogel.
  9. Mortality outcomes in diabetic metabolic dysfunction-associated fatty liver disease: non-obese versus obese individuals.
  10. Supplementation of Micro- and Macronutrients-A Role of Nutritional Status in Non-Alcoholic Fatty Liver Disease.
  11. Enhanced bioactivity and stability of a long-acting FGF21: A novel variant for the treatment of NASH.
  12. Comparative and Predictive Significance of Serum Leptin Levels in Non-alcoholic Fatty Liver Disease.
  1. Zhonghua Gan Zang Bing Za Zhi. 2024 Apr 20. 32(4): 300-302
    [Clinical status and challenges of new drugs for metabolic dysfunction-associated fatty liver disease].
    X Luo, L G Lu, Y M Mao.
      Metabolic dysfunction-associated fatty liver disease (MASLD) is a major public health problem that seriously affects human health. At present, some good progress has been made in the research and development of new drugs for MASLD, but there is still great space for exploration. This paper summarizes and analyzes the reasons in the current clinical status and challenges for the research and development of new drugs for MASLD.
    Keywords:  Clinical trials; Drug targets; Fatty liver; Metabolic dysfunction associated fatty liver disease (MASLD); Research progress
    DOI:  https://doi.org/10.3760/cma.j.cn501113-20240226-00096
  2. Heliyon. 2024 May 15. 10(9): e30387
    From NAFLD to NASH: Understanding the spectrum of non-alcoholic liver diseases and their consequences.
    Ahmed M Samy, Mohamed A Kandeil, Dina Sabry, A A Abdel-Ghany, Mohamed O Mahmoud.
      Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases worldwide in recent decades. Metabolic diseases like excessive blood glucose, central obesity, dyslipidemia, hypertension, and liver function abnormalities cause NAFLD. NAFLD significantly increases the likelihood of liver cancer, heart disease, and mortality, making it a leading cause of liver transplants. Non-alcoholic steatohepatitis (NASH) is a more advanced form of the disease that causes scarring and inflammation of the liver over time and can ultimately result in cirrhosis and hepatocellular carcinoma. In this review, we briefly discuss NAFLD's pathogenic mechanisms, their progression into NASH and afterward to NASH-related cirrhosis. It also covers disease epidemiology, metabolic mechanisms, glucose and lipid metabolism in the liver, macrophage dysfunction, bile acid toxicity, and liver stellate cell stimulation. Additionally, we consider the contribution of intestinal microbiota, genetics, epigenetics, and ecological factors to fibrosis progression and hepatocellular carcinoma risk in NAFLD and NASH patients.
    Keywords:  Cirrhosis; Gut microbiota; Metabolic disorders; NAFLD; NASH
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30387
  3. Med. 2024 May 10. pii: S2666-6340(24)00125-9. [Epub ahead of print]5(5): 375-376
    Resmetirom, the long-awaited first treatment for metabolic dysfunction-associated steatohepatitis and liver fibrosis?
    Paulina Vidal-Cevallos, Norberto Chávez-Tapia.
      The most important factor associated with liver-related mortality in NAFLD is liver fibrosis. There is no approved treatment for metabolic dysfunction-associated steatohepatitis (MASH) or liver fibrosis. In the MAESTRO-NASH trial, Harrison et al.1 demonstrated the efficacy of resmetirom, a selective THR-β agonist, for the treatment of MASH and liver fibrosis at 52 weeks.
    DOI:  https://doi.org/10.1016/j.medj.2024.03.013
  4. Zhonghua Gan Zang Bing Za Zhi. 2024 Apr 20. 32(4): 346-353
    [Analysis of non-alcoholic fatty liver disease differences from metabolic dysfunction-associated fatty liver disease based on clinical features].
    Y X Liu, F Guo, L N Niu, B Zhang, J Dou, Q Xu, Z H Ning, X Z Wang.
      Objective: To explore the clinical features of fatty liver disease (FLD) from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MASLD), so as to elucidate its clinical application value under three renames. Methods: Patients who were hospitalized in the Department of Hepatology, Hospital of Traditional Chinese Medicine Affiliated to Xinjiang Medical University, from January 2020 to September 2023 and met the diagnosis of NAFLD, metabolic-associated fatty liver disease (MAFLD), or MASLD were selected as the research subjects. The clinical indicators differences among the three groups of patients were compared, mainly including general information (age, gender, body mass index, past history, etc.), serological indicators (liver and kidney function, blood lipids, blood sugar, coagulation function, etc.), non-invasive liver fibrosis indicators, fat attenuation parameters, etc. Measurement data were analyzed using ANOVA and the rank sum test, while count data were analyzed using the χ(2) test. Results: NAFLD, MAFLD, and MASLD prevalence rates among 536 cases were 64.0%, 93.7%, and 100%, respectively. 318 cases (59.3%) met the three fatty liver names at the same time among them. Male population proportions in NAFLD, MAFLD, and MASLD were 30.9%, 55.8%, and 53.9%, respectively. The alcohol consumption history proportion was 0, 36.7%, and 36.0%, respectively. The smoking history proportion was 7.0%, 31.9%, and 30.6%, respectively. The body mass index was (27.66 ± 3.97), (28.33 ± 3.63), and (27.90 ± 3.89) kg/m(2), respectively. The γ-glutamyltransferase levels were 26.6 (18.0, 47.0) U/L, 31.0 (20.0, 53.0) U/L, and 30.8 (19.8, 30.8) U/L, respectively. The high-density lipoprotein cholesterol levels were 1.07 (0.90, 1.23) mmol/L, 1.02 (0.86, 1.19) mmol/L, and 1.03 (0.87,1.21) mmol/L, respectively. Sequentially measured uric acid was (322.98 ± 84.51) μmol/L, (346.57 ± 89.49) μmol/L, and (344.89 ±89.67) μmol/L, respectively. Sequentially measured creatinine was 69.6 (62.9, 79.0) μmol/L, 73.0 (65.0, 83.5) μmol/L, and 73.0 (65.0, 83.0) μmol/L, respectively. The sequential analysis of obesity proportion was 74.3%, 81.7%, and 76.5%, respectively, with statistically significant differences (P<0.05). Conclusion: Compared with the NAFLD population, the MAFLD and MASLD populations were predominantly male, obese, and had a history of smoking and drinking. The levels of γ-glutamyltransferase, uric acid, and creatinine were slightly higher, while the levels of high-density lipoprotein cholesterol were lower. MASLD appeared in NAFLD and MAFLD on the basis of inheritance and progression, emphasizing once again the important role of metabolic factors in a fatty liver.
    Keywords:  Differences in clinical characteristics; Fatty liver; Metabolic associated fatty liver disease; Metabolic dysfunction- associated steatotic liver disease
    DOI:  https://doi.org/10.3760/cma.j.cn501113-20231022-00153
  5. PLoS One. 2024 ;19(5): e0303296
    Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.
    Yosuke Osawa, Hironari Kawai, Keigo Nakashima, Yuichi Nakaseko, Daisuke Suto, Keisuke Yanagida, Tomomi Hashidate-Yoshida, Taizo Mori, Sachiyo Yoshio, Takaaki Ohtake, Hideo Shindou, Tatsuya Kanto.
      AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH.METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.
    RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.
    CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
    DOI:  https://doi.org/10.1371/journal.pone.0303296
  6. Toxicol Res (Camb). 2024 Jun;13(3): tfae068
    Protective effects of dopamine against non-alcoholic steatohepatitis via inhibiting p65 pathways in vivo and in vitro.
    Peng Ma, Xu Wang, Xiuqi Wen, Lingyun Pu, Yu Ou.
      Introduction: Currently, the role and mechanism of dopamine in non-alcoholic steatohepatitis (NASH) remains unclear.Methods: In vitro experiments utilized FFA and LPS to establish NASH cell models, while a fibrotic cell model was created using TGFβ1 to investigate the impact of dopamine on cellular lipid metabolism, inflammation, and fibrosis. In vivo experiments involved the use of MCD and HFD diets to induce NASH in mouse models for observing the effects of dopamine on NASH disease progression.
    Results: Our study showed that dopamine significantly downregulated the expression levels of Caspase 1, IL-1β and IL18 in the HepG2 NASH cell model. In addition, dopamine could inhibit the TGF-β1-induced accumulation of collagen I and α-SMA in LX2 cells. In vivo experiments have shown that dopamine attenuation in mice is associated with MCD diet-induced and HFD-induced steatohepatitis. Mechanically, dopamine inhibits the p65 signaling pathway in NASH.
    Conclusion: In conclusion, the present study demonstrates the role of dopamine in ameliorating the symptoms of NASH and provides a direction for future research on the application of the dopaminergic system to liver disease.
    Keywords:  dopamine; inflammasomes; non-alcoholic steatohepatitis (NASH); p65 pathway
    DOI:  https://doi.org/10.1093/toxres/tfae068
  7. Nutrients. 2024 May 02. pii: 1381. [Epub ahead of print]16(9):
    Evaluation of the Diagnostic Utility of Selected Serum Adipokines and Cytokines in Subjects with MASLD-A Pilot Study.
    Beata Zyśk, Lucyna Ostrowska, Joanna Smarkusz-Zarzecka, Karolina Orywal, Barbara Mroczko, Urszula Cwalina.
      Excess adipose tissue, particularly of the visceral type, triggering chronic low-grade inflammation and altering its secretory profile, is a contributing factor to the initiation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to compare the levels of selected adipokines and cytokines in individuals with normal weight and obesity, assessing their potential for diagnosing MASLD and establishing a cutoff point for body fat content associated with hepatic steatosis development. The research involved 99 participants categorized by body mass index and MASLD presence, undergoing body composition analysis, liver elastography, biochemical tests, and evaluation of adipokines and cytokines in serum. The results indicated elevated IL-6 (interleukin 6) serum levels in individuals with obesity with MASLD compared to the normal-weight group without MASLD. The multivariate regression analysis demonstrated a connection between hepatic steatosis and total adipose tissue content, VAT (visceral adipose tissue), VAT/SAT (subcutaneous adipose tissue) ratio, HOMA-IR (homeostasis model assessment of insulin resistance), IL-6, Il-1β (interleukin 1β), and MMP-2 (matrix metalloproteinase 2). Among the adipokines and cytokines examined in this study, interleukin 6 was the strongest predictor of MASLD regardless of gender. In addition, an association between the development of hepatic steatosis and higher serum IL-1β levels and higher adipose tissue was observed in women. However, further studies on a larger group of patients are needed to consider the use of these cytokines as markers of MASLD. The HOMA-IR index demonstrated potential diagnostic utility in identifying hepatic steatosis.
    Keywords:  Il-1β; Il-6; MASLD; NAFLD; VAT; adipokines; adipose tissue; cytokines; hepatic steatosis; visceral adipose tissue
    DOI:  https://doi.org/10.3390/nu16091381
  8. EXCLI J. 2024 ;23 421-440
    Bioengineering scalable and drug-responsive in vitro human multicellular non-alcoholic fatty liver disease microtissues encapsulated in the liver extracellular matrix-derived hydrogel.
    Negar Asadollahi, Mohammad Amin Hajari, Mahmoud Alipour Choshali, Mohammad Ajoudanian, Seyed Ali Ziai, Massoud Vosough, Abbas Piryaei.
      Non-alcoholic fatty liver disease (NAFLD) is a high-prevalence and progressive disorder. Due to lack of reliable in vitro models to recapitulate the consecutive phases, the exact pathogenesis mechanism of this disease and approved therapeutic medications have not been revealed yet. It has been proven that the interplay between multiple hepatic cell types and liver extracellular matrix (ECM) are critical in NAFLD initiation and progression. Herein, a liver microtissue (LMT) consisting of Huh-7, THP-1, and LX-2 cell lines and human umbilical vein endothelial cells (HUVEC), which could be substituted for the main hepatic cells (hepatocyte, Kupffer, stellate, and sinusoidal endothelium, respectively), encapsulated in liver derived ECM-Alginate composite, was bioengineered. When the microtissues were treated with free fatty acids (FFAs) including Oleic acid (6.6×10-4M) and Palmitic acid (3.3×10-4M), they displayed the key features of NAFLD, including similar pattern of transcripts for genes involved in lipid metabolism, inflammation, insulin-resistance, and fibrosis, as well as pro-inflammatory and pro-fibrotic cytokines' secretions and intracellular lipid accumulation. Continuing FFAs supplementation, we demonstrated that the NAFLD phenomenon was established on day 3 and progressed to the initial fibrosis stage by day 8. Furthermore, this model was stable until day 12 post FFAs withdrawal on day 3. Moreover, administration of an anti-steatotic drug candidate, Liraglutide (15 μM), on the NAFLD microtissues significantly ameliorated the NAFLD phenomenon. Overall, we bioengineered a drug-responsive, cost-benefit liver microtissues which can simulate the initiation and progression of NAFLD. It is expected that this platform could potentially be used for studying molecular pathogenesis of NAFLD and high-throughput drug screening. See also the graphical abstract(Fig. 1).
    Keywords:  bioengineering; drug screening; liraglutide; liver microtissue; metabolic dysfunction-associated fatty liver disease; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.17179/excli2023-6878
  9. Sci Rep. 2024 May 17. 14(1): 11320
    Mortality outcomes in diabetic metabolic dysfunction-associated fatty liver disease: non-obese versus obese individuals.
    Pengwei Zhang, Yijun Zeng, Sijia Yang, Chunhong Ye, Mingwei Wang, Tianfang Peng, Li Li, Xianhui Dong.
      The difference in the survival of obese patients and normal-weight/lean patients with diabetic MAFLD remains unclear. Therefore, we aimed to describe the long-term survival of individuals with diabetic MAFLD and overweight/obesity (OT2M), diabetic MAFLD with lean/normal weight (LT2M), MAFLD with overweight/obesity and without T2DM (OM), and MAFLD with lean/normal weight and without T2DM (LM). Using the NHANESIII database, participants with MAFLD were divided into four groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular disease (CVD)-related, and cancer-related mortalities for different MAFLD subtypes were evaluated using Cox proportional hazards models. Of the 3539 participants, 1618 participants (42.61%) died during a mean follow-up period of 274.41 ± 2.35 months. LT2M and OT2M had higher risks of all-cause mortality (adjusted HR, 2.14; 95% CI 1.82-2.51; p < 0.0001; adjusted HR, 2.24; 95% CI 1.32-3.81; p = 0.003) and CVD-related mortality (adjusted HR, 3.25; 95% CI 1.72-6.14; p < 0.0001; adjusted HR, 3.36; 95% CI 2.52-4.47; p < 0.0001) than did OM. All-cause and CVD mortality rates in LT2M and OT2M patients were higher than those in OM patients. Patients with concurrent T2DM and MAFLD should be screened, regardless of the presence of obesity.
    Keywords:  Metabolic (dysfunction)-associated fatty liver disease; Mortality; Normal weight; Obesity; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1038/s41598-024-61896-5
  10. Int J Mol Sci. 2024 Apr 30. pii: 4916. [Epub ahead of print]25(9):
    Supplementation of Micro- and Macronutrients-A Role of Nutritional Status in Non-Alcoholic Fatty Liver Disease.
    Magdalena Tyczyńska, Gabriela Hunek, Martyna Szczasny, Adam Brachet, Jacek Januszewski, Alicja Forma, Piero Portincasa, Jolanta Flieger, Jacek Baj.
      Non-alcoholic fatty liver disease (NAFLD) is a condition in which the pathological cumulation of fat with coexisting inflammation and damage of hepatic cells leads to progressive dysfunctions of the liver. Except for the commonly well-known major causes of NAFLD such as obesity, dyslipidemia, insulin resistance, or diabetes, an unbalanced diet and imbalanced nutritional status should also be taken into consideration. In this narrative review, we summarized the current knowledge regarding the micro- and macronutrient status of patients suffering from NAFLD considering various diets and supplementation of chosen supplements. We aimed to summarize the knowledge indicating which nutritional impairments may be associated with the onset and progression of NAFLD at the same time evaluating the potential therapy targets that could facilitate the healing process. Except for the above-mentioned objectives, one of the most important aspects of this review was to highlight the possible strategies for taking care of NAFLD patients taking into account the challenges and opportunities associated with the micronutrient status of the patients. The current research indicates that a supplementation of chosen vitamins (e.g., vitamin A, B complex, C, or D) as well as chosen elements such as zinc may alleviate the symptoms of NAFLD. However, there is still a lack of sufficient data regarding healthy ranges of dosages; thus, further research is of high importance in this matter.
    Keywords:  carotenoids; macronutrients; micronutrients; non-alcoholic fatty liver disease; nutrition; trace elements; unsaturated fats; vitamins
    DOI:  https://doi.org/10.3390/ijms25094916
  11. Biochimie. 2024 May 11. pii: S0300-9084(24)00107-X. [Epub ahead of print]
    Enhanced bioactivity and stability of a long-acting FGF21: A novel variant for the treatment of NASH.
    Yue Ji, Qingzhou Lu, Yiliang Duan, Xuan Chen, Yuxi Zhang, Wenbing Yao, Jun Yin, Xiangdong Gao.
      Fibroblast growth factor 21 (FGF21) is pivotal in regulating energy metabolism, highlighting substantial therapeutic potential for non-alcoholic steatohepatitis (NASH). Previously, we reported a long-acting FGF21 fusion protein, PsTag-FGF21, which was prepared by genetically fusing human FGF21 with a 648-residue polypeptide (PsTag). While this fusion protein demonstrated therapeutic efficacy against NASH, our final product analysis revealed the presence of fixed impurities resistant to effective removal, indicating potential degradation of PsTag-FGF21. Here, we enriched and analyzed the impurities, confirming our hypothesis regarding the C-terminal degradation of PsTag-FGF21. We now describe a new variant developed to eliminate the C-terminal degradation. By introducing one mutation located at the C-terminal of PsTag-FGF21(V169L), we demonstrated that the new molecule, PsTag-FGF21(V169L), exhibits many improved attributes. Compared with PsTag-FGF21, PsTag-FGF21(V169L) displayed elevated bioactivity and stability, along with a twofold enhanced binding affinity to the coreceptor β-Klotho. In vivo, the circulating half-life of PsTag-FGF21(V169L) was further enhanced compared with that of PsTag-FGF21. In NASH mice, PsTag-FGF21(V169L) demonstrated efficacy with sustained improvements in multiple metabolic parameters. Besides, PsTag-FGF21(V169L) demonstrated the ability to alleviate NASH by decreasing hepatocyte apoptosis. The superior biophysical, pharmacokinetic, and pharmacodynamic properties, along with the positive metabolic effects, imply that further clinical development of PsTag-FGF21(V169L) as a metabolic therapy for NASH patients may be warranted.
    Keywords:  FGF21; bioactivity; leaky E. coli; nonalcoholic steatohepatitis; recombinant polypeptide; site-specific mutation
    DOI:  https://doi.org/10.1016/j.biochi.2024.05.013
  12. Cureus. 2024 Apr;16(4): e57943
    Comparative and Predictive Significance of Serum Leptin Levels in Non-alcoholic Fatty Liver Disease.
    Mehwish Qamar, Abeer Fatima, Ambreen Tauseef, Muhammad I Yousufzai, Ibrahim Liaqat, Qanbar Naqvi.
      Background Non-alcoholic fatty liver disease (NAFLD) has emerged as the single most common chronic non-viral liver disease. The burden of the disease on healthcare-providing services has increased tremendously. Although a liver biopsy is the most authentic laboratory investigation for scoring the disease progression, it is an invasive technique. Researchers are vigorously working to find alternate markers for the scoring purpose. Despite the importance and association of leptin with metabolic syndrome and its related disorders, there have been relatively fewer studies on serum leptin and its association with NAFLD. Objective This study aimed to investigate variations in serum leptin levels between subjects with and without fibrosis in NAFLD and to assess the predictive value of serum leptin levels in NAFLD subjects. Materials and methods The study comprised 130 NAFLD subjects from two tertiary care hospitals in Lahore along with 86 healthy controls that were age, gender, and BMI matched with the subjects. Based on the NAFLD fibrosis score (NFS), the subjects were divided into two sub-groups, subjects with simple steatosis and those with fibrosis. Fasting serum leptin, glucose, and insulin levels were measured using enzyme-linked immunosorbent assay (ELISA). The Kruskal-Wallis test was applied to find differences between the three groups and Fisher's exact test for categorical comparison. To assess the predictive value of serum leptin for steatosis and fibrosis in NAFLD subjects, receiver operation characteristic (ROC) curve analysis was implemented. Results The difference in serum leptin level was statistically highly significant (p-value <0.001), with leptin levels of 10 (17.1) ng/mL among controls, 20.5 (21) ng/mL in simple steatosis, and 21 (28.6) ng/mL in fibrosis. The area under the ROC curve was 0.67 and 0.52 for steatosis and fibrosis, respectively. The cut-off value of 12.2 ng/mL showed 70% sensitivity and 50% specificity for steatosis, while at a threshold of 18 ng/mL, leptin demonstrated 40% sensitivity and specificity for fibrosis. Conclusion In conclusion, this study found that serum leptin levels are higher in NAFLD subjects compared to healthy controls, and it is a good independent predictor for the detection of liver steatosis.
    Keywords:  body fat percentage; homa-ir; insulin resistance; leptin; nafld
    DOI:  https://doi.org/10.7759/cureus.57943
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