bims-faldev 2024-06-30 papers

bims-faldev

Biomed News

on Fatty liver disease and extracellular vesicles

Issue of 2024–06–30
nine papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans.
Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.
Serum biomarkers for liver fibrosis assessment.
Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH.
Prospects and challenges of tissue-derived extracellular vesicles (Ti-EVs).
Extracellular vesicles and lipoproteins - Smart messengers of blood cells in the circulation.
A High-Fat and High-Fructose Diet Exacerbates Liver Dysfunction by Regulating Sirtuins in a Murine Model.
Impact of Peroxisome Proliferator-Activated Receptor Agonists on Myosteatosis in the Context of Metabolic Dysfunction-Associated Steatotic Liver Disease.
Extracellular vesicle-mediated protein delivery to the liver.

Int J Mol Sci. 2024 Jun 11. pii: 6420. [Epub ahead of print]25(12):

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans.

Lucia De la Cruz-Color, Jose Alfredo Dominguez-Rosales, Montserrat Maldonado-González, Bertha Ruíz-Madrigal, Martha P Sánchez Muñoz, Vianney Alejandrina Zaragoza-Guerra, Victor H Espinoza-Padilla, Elizabeth Del C Ruelas-Cinco, Sandra M Ramírez-Meza, José R Torres Baranda, María Del R González-Gutiérrez, Zamira Helena Hernandez Nazara.

  Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Keywords:  leptin; leptin receptor; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; non-alcoholic fatty liver disease; patatin-like phospholipase domain-containing protein 2; stearoyl-coa desaturase-1; sterol regulatory element-binding transcription factor 1; suppressor of cytokine signaling 3

DOI:  https://doi.org/10.3390/ijms25126420
Sci Adv. 2024 Jun 28. 10(26): eadn5228

Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.

Shalil Khanal, Yuanhang Liu, Adebowale O Bamidele, Alexander Q Wixom, Alexander M Washington, Nidhi Jalan-Sakrikar, Shawna A Cooper, Ivan Vuckovic, Song Zhang, Jun Zhong, Kenneth L Johnson, M Cristine Charlesworth, Iljung Kim, Yubin Yeon, Sangwoong Yoon, Yung-Kyun Noh, Chady Meroueh, Abdul Aziz Timbilla, Usman Yaqoob, Jinhang Gao, Yohan Kim, Fabrice Lucien, Robert C Huebert, Nissim Hay, Michael Simons, Vijay H Shah, Enis Kostallari.

Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

DOI: https://doi.org/10.1126/sciadv.adn5228
Adv Lab Med. 2024 Jun;5(2): 115-130

Serum biomarkers for liver fibrosis assessment.

Julia Maroto-García, Ana Moreno Álvarez, María P Sanz de Pedro, Antonio Buño-Soto, Álvaro González.

  Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.

Keywords:  liver fibrosis; liver fibrosis biomarkers; non-invasive biomarkers; serum biomarkers

DOI:  https://doi.org/10.1515/almed-2023-0081
J Hepatol. 2024 Jun 22. pii: S0168-8278(24)02323-7. [Epub ahead of print]

Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH.

Justine M Mucinski, Amadeo F Salvador, Mary P Moore, Talyia M Fordham, Jennifer M Anderson, Grace Shryack, Rory Cunningham, Guido Lastra, Ayman H Gaballah, Alberto Diaz-Arias, Jamal A Ibdah, R Scott Rector, Elizabeth J Parks.

   BACKGROUND & AIMS: Metabolic-dysfunction associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements.
METHODS: Following medical diagnosis of MASH, subjects were randomized to treatment (n=16) or control (n=8). Liver fat (MRS), 18-hour plasma biochemical measurements, and isotopically-labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO2peak) were also measured mid-intervention. Treatment subjects were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Control subjects continued physician-directed care.
RESULTS: Treatment induced significant (P<0.05) reductions in body weight, fat mass, and liver injury, while VO2peak (P<0.05) and fatty acid (NEFA) suppression (P=0.06) were improved. Both groups exhibited reductions in total energy intake, HbA1c, hepatic insulin resistance, and liver fat (P<0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2peak and resolution of liver disease, despite no group differences in peripheral insulin sensitivity.
CONCLUSIONS: Exercise and energy-restriction elicited significant and clinically-meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH.
CLINICAL TRIAL NUMBER: NCT03151798.

Keywords:  MASH; MASLD; NAFLD; energy restriction; exercise; histology; insulin resistance; lifestyle treatment

DOI:  https://doi.org/10.1016/j.jhep.2024.06.017
Mol Ther. 2024 Jun 22. pii: S1525-0016(24)00408-8. [Epub ahead of print]

Prospects and challenges of tissue-derived extracellular vesicles (Ti-EVs).

Justin C Lee, Roslyn M Ray, Tristan A Scott.

Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex, multicellular tissue microenvironments in biology and disease. EVs are native, lipid bilayer membrane nano-sized particles produced by all cells that are packaged with varied functional biomolecules including proteins, lipids, and nucleic acids. They are implicated in short- and long-range cellular communication and may elicit functional responses in recipient cells. To date, studies have often utilized cultured cells or biological fluids as a source for EVs that do not capture local molecular signatures of the tissue microenvironment. Recent work utilizing Ti-EVs has elucidated novel biomarkers for disease and provided insights into disease mechanisms that may lead to the development of novel therapeutic agents. Still, there are considerable challenges facing current studies. This review explores the vast potential and unique challenges for Ti-EV research and provides considerations for future studies that seek to advance this exciting field.

DOI: https://doi.org/10.1016/j.ymthe.2024.06.025
J Extracell Biol. 2022 Jul;1(7): e49

Extracellular vesicles and lipoproteins - Smart messengers of blood cells in the circulation.

Phuong H D Nguyen, Anh Hong Le, Jonetta Shi Qi Pek, Thach Tuan Pham, Migara Kavishka Jayasinghe, Dang Vinh Do, Cao Dai Phung, Minh T N Le.

  Blood cell-derived extracellular vesicles (BCEVs) and lipoproteins are the major circulating nanoparticles in blood that play an important role in intercellular communication. They have attracted significant interest for clinical applications, given their endogenous characteristics which make them stable, biocompatible, well tolerated, and capable of permeating biological barriers efficiently. In this review, we describe the basic characteristics of BCEVs and lipoproteins and summarize their implications in both physiological and pathological processes. We also outline well accepted workflows for the isolation and characterization of these circulating nanoparticles. Importantly, we highlight the latest progress and challenges associated with the use of circulating nanoparticles as diagnostic biomarkers and therapeutic interventions in multiple diseases. We spotlight novel engineering approaches and designs to facilitate the development of these nanoparticles by enhancing their stability, targeting capability, and delivery efficiency. Therefore, the present work provides a comprehensive overview of composition, biogenesis, functions, and clinical translation of circulating nanoparticles from the bench to the bedside.

Keywords:  biomarkers; drug delivery; extracellular vesicles; lipoproteins; therapeutic applications

DOI:  https://doi.org/10.1002/jex2.49
Life (Basel). 2024 Jun 05. pii: 729. [Epub ahead of print]14(6):

A High-Fat and High-Fructose Diet Exacerbates Liver Dysfunction by Regulating Sirtuins in a Murine Model.

Zehuan Ding, Jian Zhang, Mahua Choudhury.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates of diabesity. The Western diet's abundance of fat and fructose significantly contributes to MASLD, disrupting hepatic glucose metabolism. We previously demonstrated that a high-fat and high-fructose diet (HFHFD) led to increased body and liver weight compared to the low-fat diet (LFD) group, accompanied by glucose intolerance and liver abnormalities, indicating an intermediate state between fatty liver and liver fibrosis in the HFHFD group. Sirtuins are crucial epigenetic regulators associated with energy homeostasis and play a pivotal role in these hepatic dysregulations. Our investigation revealed that HFHFD significantly decreased Sirt1 and Sirt7 gene and protein expression levels, while other sirtuins remained unchanged. Additionally, glucose 6-phosphatase (G6Pase) gene expression was reduced in the HFHFD group, suggesting a potential pathway contributing to fibrosis progression. Chromatin immunoprecipitation analysis demonstrated a significant increase in histone H3 lysine 18 acetylation within the G6Pase promoter in HFHFD livers, potentially inhibiting G6Pase transcription. In summary, HFHFD may inhibit liver gluconeogenesis, potentially promoting liver fibrosis by regulating Sirt7 expression. This study offers an epigenetic perspective on the detrimental impact of fructose on MASLD progression.

Keywords:  high-fat high-fructose diet; liver fibrosis; metabolic dysfunction-associated steatotic liver disease; obesity; sirtuin

DOI:  https://doi.org/10.3390/life14060729
Discov Med. 2024 Jun;36(185): 1139-1153

Impact of Peroxisome Proliferator-Activated Receptor Agonists on Myosteatosis in the Context of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Nathan Boliaki, Guillaume Henin, Georgia Bale, Nicolas Lanthier.

   BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), and more specifically steatohepatitis may be associated with fat infiltration of skeletal muscles which is known as myosteatosis. Pan-peroxisome proliferator-activated receptor (PPAR) agonists have been shown to promote metabolic dysfunction-associated steatohepatitis (MASH) remission. However, the effect of PPAR agonists on myosteatosis remains to be determined. The aim of this review is to evaluate the effect that PPAR agonists alone or in combination, have on myosteatosis in the context of MASLD.
METHODS: Original research reports concerning the impact of PPAR agonists on muscle fat in MASLD were screened from PUBMED and EMBASE databases following the PRISMA methodology.
RESULTS: Eleven original manuscripts were included in this review. Two preclinical studies assessed the impact of the PPARα agonist on fat content in the quadriceps muscle and the liver by extracting triglycerides in rats fed a high-fat diet and in insulin-resistant mice. Both models showed muscle and liver triglyceride content reduction using WY14643. Fenofibrate had no significant impact on soleus intramyocellular lipids or liver fat content in insulin-resistant subjects based on proton magnetic resonance spectroscopy. Treatment with PPARδ agonists increased the expression of genes involved in fatty acid oxidation in two studies on muscle cell culture. PPARγ agonists were investigated in two preclinical studies and one clinical study using spectroscopy and computed tomography respectively. In the first preclinical study in Zucker diabetic fatty rats, rosiglitazone reduced muscle lipids and hepatic steatosis. In a second preclinical study using the same animal model, pioglitazone reduced tibialis anterior intramyocellular lipids. In contrast, computed tomography analyses in patients with type 2 diabetes revealed a surface area increase of low-density muscles (suggesting an increase in muscle fat content) after a one-year treatment with rosiglitazone. Varying combinations of PPAR agonists (cevoglitazar, fenofibrate/pioglitazone and muraglitazar) were evaluated in two preclinical studies and one clinical study. In rats, these treatments showed variable results for muscle and liver depending on the combinations studied. In type 2 diabetic patients, treatment with muraglitazar (a PPARα/γ agonist) reduced the intramyocellular lipid content of tibialis anterior as well as liver fat content following spectroscopy assessment.
CONCLUSION: The combination of different PPAR agonists could have a positive impact on reducing myosteatosis, in addition to their effect on the liver. Some discrepancies could be explained by the different techniques used to assess muscle lipid content, the muscles assessed and the possible adipogenic effect of PPARγ agonists. Further clinical research is needed to fully assess the efficacy of these treatments on both MASLD progression and associated myosteatosis.

Keywords:  MASLD; PPAR; insulin resistance; lanifibranor; muscle; muscle fat; myokine; myosteatosis

DOI:  https://doi.org/10.24976/Discov.Med.202436185.104
J Extracell Biol. 2023 Sep;2(9): e97

Extracellular vesicle-mediated protein delivery to the liver.

Nazma F Ilahibaks, Marieke T Roefs, Maike A D Brans, Christian Snijders Blok, Saskia C A de Jager, Raymond M Schiffelers, Pieter Vader, Zhiyong Lei, Joost P G Sluijter.

  Extracellular vesicles (EVs) are nanoscale particles that facilitate intercellular communication. They are regarded as a promising natural drug delivery system for transporting and delivering bioactive macromolecules to target cells. Recently, researchers have engineered EVs with FKBP12/FRB heterodimerization domains that interact with rapamycin to load and deliver exogenous proteins for both in vitro and in vivo applications. In this study, we examined the tissue distribution of EVs using near-infrared fluorescent imaging. We evaluated the effectiveness of EV-mediated delivery of Cre recombinase specifically to hepatocytes in the livers of Ai9 Cre-loxP reporter mice. Intravenous injection resulted in more efficient Cre protein delivery to the liver than intraperitoneal injections. Depleting liver-resident macrophages with clodronate-encapsulated liposome pre-treatment did not enhance EV-mediated Cre delivery to hepatocytes. Moreover, we demonstrated that multiple intravenous injections of Cre-EVs facilitated functional Cre delivery to hepatocytes. To the best of our knowledge, this is the first study to simultaneously investigate the tissue distribution of FKBP12/FRB-engineered EVs and their subsequent intracellular protein delivery in Ai9 Cre-loxP reporter mice. These insights can inform preclinical research and contribute to developing next-generation EV-based platforms for delivering therapeutic proteins or genome editing technologies targeting the liver.

Keywords:  EV uptake; EV‐mediated drug delivery; drug delivery; exosomes; extracellular vesicles; microvesicles; protein delivery

DOI:  https://doi.org/10.1002/jex2.97