bims-faldev Biomed News
on Fatty liver disease and extracellular vesicles
Issue of 2024‒06‒02
thirteen papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas
  1. Serum miR‑29 is increased in mice with early liver fibrosis.
  2. RNA modifications in the progression of liver diseases: from fatty liver to cancer.
  3. Single-Cell Data Analysis Reveals Critical Hepatic Cells Subpopulations in the Progression of Non-alcoholic Fatty Liver Disease to Non-Alcoholic Steatohepatitis.
  4. [Research progress on induced hepatic stellate cell ferroptosis in prevention and treatment of liver fibrosis].
  5. Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice.
  6. Monitoring disease progression in metabolic dysfunction-associated steatotic liver disease.
  7. Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-Associated Steatohepatitis Development.
  8. Lipotoxic hepatocyte derived LIMA1 enriched small extracellular vesicles promote hepatic stellate cells activation via inhibiting mitophagy.
  9. A Novel Mutation in LXRα Uncovers a Role for Cholesterol Sensing in Limiting Metabolic Dysfunction-Associated Steatohepatitis (MASH).
  10. Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo.
  11. Insulin-degrading enzyme inhibition increases the unfolded protein response and favours lipid accumulation in the liver.
  12. Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD.
  13. SIRT1 regulates hepatic vldlr levels.
  1. Exp Ther Med. 2024 Jul;28(1): 285
    Serum miR‑29 is increased in mice with early liver fibrosis.
    Kana Matsumoto, Yuhei Ohsugi, Chisa Tayama, Momone Hayashi, Yumiko Kato, Mizuho Ohashi, Mitsuru Chiba.
      Non-alcoholic steatohepatitis (NASH) is a fatty liver disease that is not caused by alcohol consumption and is characterized by fatty degeneration, inflammation and hepatocellular damage. Therefore, predicting future fibrosis is critical in the early stages of NASH to prevent disease progression. The present study examined histological changes in the liver as well as microRNA (miR/miRNA) expression changes in the liver and serum of NASH mice model to identify potential biomarker candidates that could predict early fibrosis. This study used 6-week-old C57BL/6NJcl male mice and fed the control with a standard solid diet (CE-2) for breeding and propagation and NASH groups with a high-fat diet [choline-deficient high-fat and 0.1% (w/v) methionine supplemented diet], respectively. Agilent Technologies miRNA microarray was used to investigate microRNA expression in the liver and serum. Hematoxylin and eosin staining of the livers of the NASH group mice during the second week of feeding revealed fatty degeneration, balloon-like degeneration and inflammatory cell infiltration, confirming that the mice were in a state of NASH. The livers of the NASH group mice at 6 weeks of feeding showed fibrosis. Microarray analysis revealed that miRNAs were upregulated and 47 miRNAs were downregulated in the liver of the NASH group. Pathway analysis using OmicsNet predicted miR-29 to target collagen genes. Furthermore, miR-29 was downregulated in the livers of NASH-induced mice but upregulated in serum. These findings suggested that lower miR-29 expression in NASH-induced liver would increase collagen expression and fibrosis. Early liver fibrosis suggests that miR-29 leaks from the liver into the bloodstream, and elevated serum miR-29 levels may be a predictive biomarker for early liver fibrosis.
    Keywords:  fibrosis; gene expression; microRNA; microRNA-29; microarray; serum
    DOI:  https://doi.org/10.3892/etm.2024.12573
  2. Sci China Life Sci. 2024 May 27.
    RNA modifications in the progression of liver diseases: from fatty liver to cancer.
    Simiao Li, Wajahat Z Mehal, Xinshou Ouyang.
      Non-alcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern associated with high risk of metabolic syndrome, and has impacted a substantial segment of the population. The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is increasingly becoming a prevalent indication for liver transplantation. The existing therapeutic options for NAFLD, NASH, and HCC are limited, underscoring the urgent need for innovative treatment strategies. Insights into gene expression, particularly RNA modifications such as N6 methyladenosine (m6A), hold promising avenues for interventions. These modifications play integral roles in RNA metabolism and cellular functions, encompassing the entire NAFLD-NASH-HCC progression. This review will encompass recent insights on diverse RNA modifications, including m6A, pseudouridine (ψ), N1-methyladenosine (m1A), and 5-methylcytidine (m5C) across various RNA species. It will uncover their significance in crucial aspects such as steatosis, inflammation, fibrosis, and tumorigenesis. Furthermore, prospective research directions and therapeutic implications will be explored, advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.
    Keywords:  HCC; NAFLD; NASH; fatty liver; m6A RNA modification
    DOI:  https://doi.org/10.1007/s11427-023-2494-x
  3. Comb Chem High Throughput Screen. 2024 May 27.
    Single-Cell Data Analysis Reveals Critical Hepatic Cells Subpopulations in the Progression of Non-alcoholic Fatty Liver Disease to Non-Alcoholic Steatohepatitis.
    Cuijuan Zhao, Guixian Ji, Xingliang Zhao, Tengqi Ma, Yanhua Li, Wenbo Wu, Lu Zhou.
      AIMS: The aim of this study was to reveal the hepatic cell landscape and function in the progression of NAFLD to NASH.BACKGROUND: Non-alcoholic steatohepatitis (NASH) is the progressive form and turning point of nonalcoholic fatty liver disease (NAFLD), which severely causes irreversible cirrhosis as well as hepatocellular carcinoma. The mechanism underlying the progression of NAFLD to NASH has not been revealed. Unraveling the mechanism of action of NAFLD-NASH is an important goal in improving the survival of patients with liver disease.
    OBJECTIVE: The aim of this study is to discover heterogeneous hepatic cells during the progression of NAFLD to NASH.
    METHODS: Single-nucleus RNA-seq (snRNA-seq) data containing NASH in NAFLD samples were obtained from the Gene Expression Omnibus (GEO) database. Cell types in liver tissues from NASH and NAFLD were identified after dimensionality reduction analysis, cluster analysis, and cell annotation. The cell pathways in which differences existed were identified by analyzing metabolic pathways in Hepatic cells. We also identified cell subpopulations in Hepatic cells. The developmental trajectories of Hepatic cells were characterized by pseudotime trajectory analysis. Single-cell regulatory network inference and clustering analysis identified key transcription factors and gene regulatory networks in Hepatic cells. Moreover, cell communication analysis determined the potential interactions between Hepatic cells and immune cells, and heapatic stellate cells.
    RESULTS: Seven cell types were identified in NAFLD and NASH. The proportion of Hepatic cells was lower in NASH and showed greater energy metabolism and glucose metabolism activity. Hepatic cells exhibited heterogeneity, showing two cell subpopulations, Hepatic cells 1 and Hepatic cells 2. Dysregulation of lipid metabolism in Hepatic Cell 2 resulted in lipid accumulation in the liver, which might be involved in the progression of NAFLD. Four key transcription factors, BHLHE40, NFEL2L, RUNX1, and INF4A, were primarily found in Hepatic cells 2. The transcription factors within the hepatic cells 2 subpopulation mainly regulated genes related to lipid metabolism, energy metabolism, and inflammatory response. The cell communication analysis showed that hepatocyte interactions with immune cells were associated with inflammatory responses, while interactions with hepatic astrocytes were associated with liver injury and hepatocyte fibrosis.
    CONCLUSION: The hepatic cells 2 might promote the progression of NAFLD to NASH by regulating metabolic activity, which might contribute to liver injury through inflammation.
    Keywords:  Hepatic cells; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; cell communication; cellular heterogeneity.; snRNA-seq
    DOI:  https://doi.org/10.2174/0113862073303213240523095742
  4. Zhongguo Zhong Yao Za Zhi. 2024 May;49(9): 2281-2289
    [Research progress on induced hepatic stellate cell ferroptosis in prevention and treatment of liver fibrosis].
    Yuan-Yuan Niu, Ze-Kun Fan, Long-de Wang, Zheng-Ju Li, Xiao-Juan DU, Wen-Juan Xu, Lin-Jing Guo.
      Liver fibrosis is a key pathological stage in the progression of chronic liver disease. If the disease is mistreated, it can further deteriorate into liver failure, which seriously affects the quality of life of patients and brings heavy medical costs. Hepatic stellate cell(HSC) activation triggers extracellular matrix(ECM) deposition, which plays an important driving role in liver fibrosis, and ferroptosis is an effective strategy to clear or reverse the activation of HSCs into a deactivated phenotype. Therefore, inhibiting the activation and proliferation of HSCs by regulating ferroptosis is the key to the treatment of this disease, so as to derive the prospect of inducing ferroptosis of HSCs(including RNA-binding proteins, non-coding RNA, chemicals, and active components of traditional Chinese medicine) to intervene in liver fibrosis. On this basis, this paper started from the activation of HSCs to induce ECM deposition and focused on summarizing the mechanism of inducing HSC ferroptosis in delaying the progression of liver fibrosis, so as to continuously enrich the clinical practice of liver fibrosis and provide a reference for subsequent basic research.
    Keywords:  ECM deposition; HSC activation; active components of traditional Chinese medicine; ferroptosis; liver fibrosis; non-coding RNA
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20240208.601
  5. Mol Metab. 2024 May 28. pii: S2212-8778(24)00093-0. [Epub ahead of print] 101962
    Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice.
    Marcos F Fondevila, Eva Novoa, Uxia Fernandez, Valentina Dorta, Tamara Parracho, Henriette Kreimeyer, Maria Garcia-Vence, Maria P Chantada-Vazquez, Susana B Bravo, Begoña Porteiro, Alba Cabaleiro, Mijra Koning, Ana Senra, Yara Souto, Joanne Verheij, Diana Guallar, Miguel Fidalgo, Abraham S Meijnikman, Natalia da Silva Lima, Carlos Dieguez, Maria J Gonzalez-Rellan, Ruben Nogueiras.
      OBJECTIVE: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown.METHODS: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63.
    RESULTS: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline- deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance.
    CONCLUSIONS: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.
    Keywords:  MASH; MASLD; NAFLD; NASH; TAp63; fibrosis; liver; metabolism; p63; steatosis
    DOI:  https://doi.org/10.1016/j.molmet.2024.101962
  6. Aliment Pharmacol Ther. 2024 Jun;59 Suppl 1 S41-S51
    Monitoring disease progression in metabolic dysfunction-associated steatotic liver disease.
    Nabil Noureddin, Nedret Copur-Dahi, Rohit Loomba.
      BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease. Its prevalence is increasing with the epidemic of obesity and metabolic syndrome. MASLD progression into metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis may lead to decompensated cirrhosis and development of liver-related events, hepatocellular carcinoma and death. Monitoring disease progression is critical in decreasing morbidity, mortality, need for transplant and economic burden. Assessing for treatment response once FDA-approved medications are available is still an unmet clinical need.AIMS: To explore the most up-to-date literature on testing used for monitoring disease progression and treatment response METHODS: We searched PubMed from inception to 15 August 2023, using the following MeSH terms: 'MASLD', 'Metabolic dysfunction-associated steatotic liver disease', 'MASH', 'metabolic dysfunction-associated steatohepatitis', 'Non-Alcoholic Fatty Liver Disease', 'NAFLD', 'non-alcoholic steatohepatitis', 'NASH', 'Biomarkers', 'clinical trial'. Articles were also identified through searches of the authors' files. The final reference list was generated based on originality and relevance to this review's broad scope, considering only papers published in English.
    RESULTS: We have cited 101 references in this review detailing methods to monitor MASLD disease progression and treatment response.
    CONCLUSION: Various biomarkers can be used in different care settings to monitor disease progression. Further research is needed to validate noninvasive tests more effectively.
    Keywords:  ascites; hepatic encephalopathy; hepatocellular carcinoma; metabolic dysfunction‐associated steatotic liver disease (MASLD); nonalcoholic fatty liver disease (NAFLD); varices
    DOI:  https://doi.org/10.1111/apt.17752
  7. Cell Mol Gastroenterol Hepatol. 2024 May 24. pii: S2352-345X(24)00119-X. [Epub ahead of print] 101365
    Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-Associated Steatohepatitis Development.
    Ryan J Dashek, Rory P Cunningham, Christopher L Taylor, Isabella Alessi, Connor Diaz, Grace M Meers, Andrew A Wheeler, Jamal A Ibdah, Elizabeth J Parks, Tadashi Yoshida, Bysani Chandrasekar, R Scott Rector.
      BACKGROUND AND AIMS: REversion inducing Cysteine rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood.METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis.
    RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild type mice. Hepatocyte-RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (A Disintegrin And Metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation.
    CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlight its potential as a novel therapeutic in MASH.
    Keywords:  MASH; MASLD; NAFLD; NASH; amphiregulin; epidermal growth factor receptor; extracellular matrix; fatty liver disease; reversion inducing cysteine rich protein with kazal motifs; steatosis
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.101365
  8. Cell Mol Biol Lett. 2024 May 31. 29(1): 82
    Lipotoxic hepatocyte derived LIMA1 enriched small extracellular vesicles promote hepatic stellate cells activation via inhibiting mitophagy.
    Shihui Li, Fuji Yang, Fang Cheng, Ling Zhu, Yongmin Yan.
      BACKGROUND: Hepatic stellate cells (HSCs) play a crucial role in the development of fibrosis in non-alcoholic fatty liver disease (NAFLD). Small extracellular vesicles (sEV) act as mediators for intercellular information transfer, delivering various fibrotic factors that impact the function of HSCs in liver fibrosis. In this study, we investigated the role of lipotoxic hepatocyte derived sEV (LTH-sEV) in HSCs activation and its intrinsic mechanisms.METHODS: High-fat diet (HFD) mice model was constructed to confirm the expression of LIMA1. The relationship between LIMA1-enriched LTH-sEV and LX2 activation was evaluated by measurement of fibrotic markers and related genes. Levels of mitophagy were detected using mt-keima lentivirus. The interaction between LIMA1 and PINK1 was discovered through database prediction and molecular docking. Finally, sEV was injected to investigate whether LIMA1 can accelerate HFD induced liver fibrosis in mice.
    RESULTS: LIMA1 expression was upregulated in lipotoxic hepatocytes and was found to be positively associated with the expression of the HSCs activation marker α-SMA. Lipotoxicity induced by OPA led to an increase in both the level of LIMA1 protein in LTH-sEV and the release of LTH-sEV. When HSCs were treated with LTH-sEV, LIMA1 was observed to hinder LX2 mitophagy while facilitating LX2 activation. Further investigation revealed that LIMA1 derived from LTH-sEV may inhibit PINK1-Parkin-mediated mitophagy, consequently promoting HSCs activation. Knocking down LIMA1 significantly attenuates the inhibitory effects of LTH-sEV on mitophagy and the promotion of HSCs activation.
    CONCLUSIONS: Lipotoxic hepatocyte-derived LIMA1-enriched sEVs play a crucial role in promoting HSCs activation in NAFLD-related liver fibrosis by negatively regulating PINK1 mediated mitophagy. These findings provide new insights into the pathological mechanisms involved in the development of fibrosis in NAFLD.
    Keywords:  Hepatic stellate cells; LIMA1; Mitophagy; Nonalcoholic fatty liver disease; Small extracellular vesicles
    DOI:  https://doi.org/10.1186/s11658-024-00596-4
  9. bioRxiv. 2024 May 15. pii: 2024.05.13.593869. [Epub ahead of print]
    A Novel Mutation in LXRα Uncovers a Role for Cholesterol Sensing in Limiting Metabolic Dysfunction-Associated Steatohepatitis (MASH).
    Alexis T Clark, Lillian Russo-Savage, Luke A Ashton, Niki Haghshenas, Ira G Schulman.
      Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease.
    DOI:  https://doi.org/10.1101/2024.05.13.593869
  10. World J Gastroenterol. 2024 May 07. 30(17): 2369-2370
    Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo.
    Takeshi Suda.
      Exosomes, the smallest extracellular vesicles, have gained significant attention as key mediators in intercellular communication, influencing both physiological and pathological processes, particularly in cancer progression. A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes, with a focus on the origin from which exosomes derive. If information about the mechanisms for delivering exosomes to specific cells is incorporated, the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.
    Keywords:  Exosomal delivery; Hepatocellular carcinoma; MicroRNAs; Therapeutic targets
    DOI:  https://doi.org/10.3748/wjg.v30.i17.2369
  11. Br J Pharmacol. 2024 May 29.
    Insulin-degrading enzyme inhibition increases the unfolded protein response and favours lipid accumulation in the liver.
    Marine Andres, Nathalie Hennuyer, Khamis Zibar, Marie Bicharel-Leconte, Isabelle Duplan, Emmanuelle Enée, Emmanuelle Vallez, Adrien Herledan, Anne Loyens, Bart Staels, Benoit Deprez, Peter van Endert, Rebecca Deprez-Poulain, Steve Lancel.
      BACKGROUND AND PURPOSE: Nonalcoholic fatty liver disease refers to liver pathologies, ranging from steatosis to steatohepatitis, with fibrosis ultimately leading to cirrhosis and hepatocellular carcinoma. Although several mechanisms have been suggested, including insulin resistance, oxidative stress, and inflammation, its pathophysiology remains imperfectly understood. Over the last decade, a dysfunctional unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress emerged as one of the multiple driving factors. In parallel, growing evidence suggests that insulin-degrading enzyme (IDE), a highly conserved and ubiquitously expressed metallo-endopeptidase originally discovered for its role in insulin decay, may regulate ER stress and UPR.EXPERIMENTAL APPROACH: We investigated, by genetic and pharmacological approaches, in vitro and in vivo, whether IDE modulates ER stress-induced UPR and lipid accumulation in the liver.
    KEY RESULTS: We found that IDE-deficient mice display higher hepatic triglyceride content along with higher inositol-requiring enzyme 1 (IRE1) pathway activation. Upon induction of ER stress by tunicamycin or palmitate in vitro or in vivo, pharmacological inhibition of IDE, using its inhibitor BDM44768, mainly exacerbated ER stress-induced IRE1 activation and promoted lipid accumulation in hepatocytes, effects that were abolished by the IRE1 inhibitors 4μ8c and KIRA6. Finally, we identified that IDE knockout promotes lipolysis in adipose tissue and increases hepatic CD36 expression, which may contribute to steatosis.
    CONCLUSION AND IMPLICATIONS: These results unravel a novel role for IDE in the regulation of ER stress and development of hepatic steatosis. These findings pave the way to innovative strategies modulating IDE to treat metabolic diseases.
    Keywords:  MASLD; endoplasmic reticulum stress; insulin‐degrading enzyme; liver; unfolded protein response
    DOI:  https://doi.org/10.1111/bph.16436
  12. Nat Commun. 2024 May 29. 15(1): 4564
    Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD.
    Lars Verschuren, Anne Linde Mak, Arianne van Koppen, Serdar Özsezen, Sonia Difrancesco, Martien P M Caspers, Jessica Snabel, David van der Meer, Anne-Marieke van Dijk, Elias Badal Rashu, Puria Nabilou, Mikkel Parsberg Werge, Koen van Son, Robert Kleemann, Amanda J Kiliaan, Eric J Hazebroek, André Boonstra, Willem P Brouwer, Michail Doukas, Saurabh Gupta, Cornelis Kluft, Max Nieuwdorp, Joanne Verheij, Lise Lotte Gluud, Adriaan G Holleboom, Maarten E Tushuizen, Roeland Hanemaaijer.
      Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.
    DOI:  https://doi.org/10.1038/s41467-024-48956-0
  13. Cell Commun Signal. 2024 May 28. 22(1): 297
    SIRT1 regulates hepatic vldlr levels.
    Mona Peyman, Anna Babin-Ebell, Rosalía Rodríguez-Rodríguez, Matilde Rigon, David Aguilar-Recarte, Joan Villarroya, Anna Planavila, Francesc Villarroya, Xavier Palomer, Emma Barroso, Manuel Vázquez-Carrera.
      BACKGROUND: Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins.METHODS: Rats fed with fructose in drinking water, Sirt1-/- mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used.
    RESULTS: Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1-/- mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin.
    CONCLUSIONS: Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.
    Keywords:  ER stress; HIF-1α; MASLD; SIRT1; VLDLR
    DOI:  https://doi.org/10.1186/s12964-024-01666-y
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