bims-faldev 2024-05-26 papers

bims-faldev

Biomed News

on Fatty liver disease and extracellular vesicles

Issue of 2024–05–26
fiveteen papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas

The Transition in Terminology: From Non-alcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) to Metabolic-associated Steatotic Liver Disease (MASLD).
Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration.
Cardiometabolic and Metabolic Profiles of Lean/Normal, Overweight and Obese Patients with Nonalcoholic Fatty Liver Disease.
Increased phosphatidylcholine and its hydroperoxides in serum low-density lipoproteins from patients with non-alcoholic steatohepatitis.
Helper Lipid-Enhanced mRNA Delivery for Treating Metabolic Dysfunction-Associated Fatty Liver Disease.
Before Translating Extracellular Vesicles into Personalized Diagnostics and Therapeutics: What We Could Do.
Can Nutraceuticals Support the Treatment of MASLD/MASH, and thus Affect the Process of Liver Fibrosis?
Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications.
Bioengineering extracellular vesicle cargo for optimal therapeutic efficiency.
Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?
Animal studies of sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease.
Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma.
Biological rhythms of the liver.
The Role of Extracellular Vesicles in Metabolic Diseases.
Pharmacological inhibition of p300 ameliorates steatosis, inflammation, and fibrosis in mice with non-alcoholic steatohepatitis.

J Hepatol. 2024 May 22. pii: S0168-8278(24)00359-3. [Epub ahead of print]

The Transition in Terminology: From Non-alcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) to Metabolic-associated Steatotic Liver Disease (MASLD).

Linda Henry, James M Paik, Zobair M Younossi.

DOI: https://doi.org/10.1016/j.jhep.2024.05.024
World J Gastroenterol. 2024 May 14. 30(18): 2387-2390

Metabolic dysfunction-associated steatotic liver disease: Navigating terminological evolution, diagnostic frontiers and therapeutic horizon-an editorial exploration.

Aleksandra Boldys, Lukasz Buldak.

  Metabolic dysfunction-associated steatotic liver disease (MASLD), once known as non-alcoholic fatty liver disease (NAFLD), represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes. The redefinition of NAFLD in 2023 marked a significant reposition in terminology, emphasizing a broader understanding of liver steatosis and its associated risks. MASLD is now recognized as a major risk factor for liver cirrhosis, hepatocellular carcinoma, and systemic complications such as cardiovascular diseases or systemic inflammation. Diagnostic challenges arise, particularly in identifying MASLD in lean individuals, necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools. Therapeutically, there is an urgent need for effective treatments targeting MASLD, with emerging pharmacological options focusing on, among others, carbohydrate and lipid metabolism. Additionally, understanding the roles of bile acid metabolism, the microbiome, and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches. There is a strong need to emphasize the importance of collaborative efforts in understanding, diagnosing, and managing MASLD to improve physicians' approaches and patient outcomes.

Keywords:  Diagnostics; Metabolic dysfunction-associated steatotic liver disease; Pathophysiology of metabolic dysfunction-associated steatotic liver disease; Therapeutic innovations; Therapy of metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.3748/wjg.v30.i18.2387
Diabetes Metab Syndr Obes. 2024 ;17 2027-2036

Cardiometabolic and Metabolic Profiles of Lean/Normal, Overweight and Obese Patients with Nonalcoholic Fatty Liver Disease.

Siyao Wang, Yong Zhang, Xiaoya Qi, Xiaoyang Xu.

   Purpose: Disagreements about the risk of non-obese, non-alcoholic fatty liver disease for cardiometabolic outcomes occurred widely. This study aims to characterize the cardiometabolic and metabolic profile of lean/normal, overweight and obese patients with nonalcoholic fatty liver disease on a big sample.
Patients and methods: Appeared healthy adults who participated in health examinations during the year of 2019-2022 were screened for fatty liver diagnosis. BMI classified fatty livers as lean, overweight and obese. Eleven cardiometabolic metrics (SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglycerides; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol) and metabolic metrics (GLU: blood glucose; GHB: glycated haemoglobin; UA: uric acid; AST: aspartate aminotransferase; ALT: alanine aminotransferase) were included, described and compared among BMI categories.
Results: There were 56,496 fatty livers diagnosed by ultrasound in this study. In total, the lean fatty liver had lowest mean SBP, DBP, GLU, TG, UA, AST, and ALT but highest TC and HDL among BMI categories (all p < 0.001). The number of abnormal metrics in total was 2.5, 2.9 and 3.4 in lean, overweight, and obesity, respectively (p < 0.001, p_trend < 0.001). Visualized data showed that lean fatty liver was similar but milder in all metabolic metrics than overweight and obesity at the young ages. However, lean fatty liver had higher coefficients of age and risk of metabolic abnormality regression (p <0.001 for SBP, DBP, GLU, GHB, TC).
Conclusion: The lean type of fatty livers at a younger age has a relatively favourable cardiometabolic and metabolic profile compared to overweight and obese fatty livers. Due to the possible catch-up effect of metabolic dysfunctions in young lean fatty liver, lean fatty liver may have the same health outcomes as overweight/obesity fatty liver in long term. The evaluation and intervention may be critical for young lean fatty liver management to slowdown the rapid progress of metabolic dysfunction.

Keywords:  body mass index; cardiometabolic profile; fatty liver; metabolic profile

DOI:  https://doi.org/10.2147/DMSO.S462003
Ann Clin Biochem. 2024 May 23. 45632241259658

Increased phosphatidylcholine and its hydroperoxides in serum low-density lipoproteins from patients with non-alcoholic steatohepatitis.

Nanao Murakami, Toshihiro Sakurai, Arisa Yamahata, Akiko Sakurai, Kazuhiro Nouso, Yuki Fujii, Hitoshi Chiba, Shu-Ping Hui.

   BACKGROUND: Non-alcoholic fatty liver disease is classified into simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) according to histological findings from liver biopsies. Phosphatidylcholine (PC), the main component of phospholipids in serum lipoproteins, is easily oxidized to phosphatidylcholine hydroperoxide (PC-OOH). Although a lipid composition in the low-density lipoproteins (LDL) from patients with NASH could be abnormal, it remains unclear. Here, to better understand the characteristics of lipids in the LDL from NASH and SS, we compared the composition of PC and PC-OOH species in LDL particles (LDL-PC, LDL-PCOOH) from these patients, then clarified the association between these lipids and NASH severity.
METHODS: The serum samples from patients with NASH (female, n = 9) and SS (female, n = 4; male, n = 2) were used for isolation of LDL. Total lipids were extracted from isolated LDL, and the species of PC and PC-OOH were measured using liquid chromatography-mass spectrometry/mass spectrometry.
RESULTS: The sum of LDL-PC and the sum of LDL-PCOOH were significantly higher in NASH than in SS. Several LDL-PC (PC 32:0, 32:1, 32:2, 34:3, 36:2, sum of PC with saturated fatty acyl chains and sum of LDL-PC with polyunsaturated fatty acyl chains) and several LDL-PCOOH (34:2, 36:2, 36:3 and total) were increased significantly with increasing fibrosis score. In particular, a series of LDL-PCOOH were more reflective of the severity of fibrosis score.
CONCLUSIONS: LDL-PC and LDL-PCOOH species were strongly correlated with the fibrosis score in NASH, which suggests that abnormal LDL is involved in the development of liver fibrosis.

Keywords:  Analytes; Clinical studies; Laboratory methods; Lipids; Liver disease; Mass spectrometry

DOI:  https://doi.org/10.1177/00045632241259658
Nano Lett. 2024 May 23.

Helper Lipid-Enhanced mRNA Delivery for Treating Metabolic Dysfunction-Associated Fatty Liver Disease.

Zixuan Guo, Cici Zeng, Yanqiong Shen, Lei Hu, Haiyan Zhang, Zhibin Li, Wang Dong, Qin Wang, Qi Liu, Yucai Wang, Wei Jiang.

  Lipid nanoparticles (LNPs) represent the forefront of mRNA delivery platforms, yet achieving precise delivery to specific cells remains a challenge. The current targeting strategies complicate the formulation and impede the regulatory approval process. Here, through a straightforward regulation of helper lipids within LNPs, we introduce an engineered LNP designed for targeted delivery of mRNA into hepatocytes for metabolic dysfunction-associated fatty liver disease (MAFLD) treatment. The optimized LNP, supplied with POPC as the helper lipid, exhibits a 2.49-fold increase in mRNA transfection efficiency in hepatocytes compared to that of FDA-approved LNPs. CTP:phosphocholine cytidylyltransferase α mRNA is selected for delivery to hepatocytes through the optimized LNP system for self-calibration of phosphatidylcholine levels to prevent lipid droplet expansion in MAFLD. This strategy effectively regulates lipid homeostasis, while demonstrating proven biosafety. Our results present a mRNA therapy for MAFLD and open a new avenue for discovering potent lipids enabling mRNA delivery to specific cells.

Keywords:  MAFLD; helper lipid; hepatocyte-selective; lipid nanoparticle; mRNA delivery

DOI:  https://doi.org/10.1021/acs.nanolett.4c01458
Mol Pharm. 2024 May 21.

Before Translating Extracellular Vesicles into Personalized Diagnostics and Therapeutics: What We Could Do.

Chi-An Cheng.

  Extracellular vesicle (EV) research is rapidly advancing from fundamental science to translational applications in EV-based personalized therapeutics and diagnostics. Yet, fundamental questions persist regarding EV biology and mechanisms, particularly concerning the heterogeneous interactions between EVs and cells. While we have made strides in understanding virus delivery and intracellular vesicle transport, our comprehension of EV trafficking remains limited. EVs are believed to mediate intercellular communication through cargo transfer, but uncertainties persist regarding the occurrence and quantification of EV-cargo delivery within acceptor cells. This ambiguity is crucial to address, given the significant translational impact of EVs on therapeutics and diagnostics. This perspective article does not seek to provide exhaustive recommendations and guidance on EV-related studies, as these are well-articulated in position papers and statements by the International Society for Extracellular Vesicles (ISEV), including the 'Minimum Information for Studies of Extracellular Vesicles' (MISEV) 2014, MISEV2018, and the recent MISEV2023. Instead, recognizing the multilayered heterogeneity of EVs as both a challenge and an opportunity, this perspective emphasizes novel approaches to facilitate our understanding of diverse EV biology, address uncertainties, and leverage this knowledge to advance EV-based personalized diagnostics and therapeutics. Specifically, this perspective synthesizes current insights, identifies opportunities, and highlights exciting technological advancements in ultrasensitive single EV or "digital" profiling developed within the author's multidisciplinary group. These newly developed technologies address technical gaps in dissecting the molecular contents of EV subsets, contributing to the evolution of EVs as next-generation liquid biopsies for diagnostics and providing better quality control for EV-based therapeutics.

Keywords:  diagnostics; drug delivery; exosome; extracellular vesicle; personalized medicine; protein biomarker; single molecule array

DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c00185
Int J Mol Sci. 2024 May 11. pii: 5238. [Epub ahead of print]25(10):

Can Nutraceuticals Support the Treatment of MASLD/MASH, and thus Affect the Process of Liver Fibrosis?

Aneta Sokal-Dembowska, Sara Jarmakiewicz-Czaja, Katarzyna Ferenc, Rafał Filip.

  Currently, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are considered to be the main causes of fibrosis. In turn, fibrosis may lead to the development of hepatocellular carcinoma or advanced cirrhosis, i.e., potentially life-threatening conditions. It is likely that therapy aimed at reducing the risk of developing hepatic steatosis and inflammation could be helpful in minimizing the threat/probability of organ fibrosis. In recent years, increasing attention has been paid to the influence of nutraceuticals in the prevention and treatment of liver diseases. Therefore, the aim of this review was to describe the precise role of selected ingredients such as vitamin C, beta-carotene, omega-3 fatty acids, and curcumin. It is likely that the use of these ingredients in the treatment of patients with MASLD/MASH, along with behavioral and pharmacological therapy, may have a beneficial effect on combating inflammation, reducing oxidative stress, and thereby preventing liver damage.

Keywords:  antioxidants; beta-carotene; curcumin; liver fibrosis; nutraceuticals; omega-3 fatty acids

DOI:  https://doi.org/10.3390/ijms25105238
Biomed Pharmacother. 2024 May 17. pii: S0753-3322(24)00608-5. [Epub ahead of print]175 116724

Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications.

Lili Yu, Feifei Gao, Yaoxin Li, Dan Su, Liping Han, Yueming Li, Xuehan Zhang, Zhiwei Feng.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.

Keywords:  C-type lectin receptors (CLRs); DNA sensors; Metabolic dysfunction-associated steatotic liver disease (MAFLD); NOD-like receptors (NLRs); Pattern recognition receptor; RIG-like receptors (RLRs); Toll-like receptors (TLRs)

DOI:  https://doi.org/10.1016/j.biopha.2024.116724
Mol Ther Methods Clin Dev. 2024 Jun 13. 32(2): 101259

Bioengineering extracellular vesicle cargo for optimal therapeutic efficiency.

Charlotte A René, Robin J Parks.

  Extracellular vesicles (EVs) have the innate ability to carry proteins, lipids, and nucleic acids between cells, and thus these vesicles have gained much attention as potential therapeutic delivery vehicles. Many strategies have been explored to enhance the loading of specific cargoes of interest into EVs, which could result in the delivery of more therapeutic to recipient cells, thus enhancing therapeutic efficacy. In this review, we discuss the natural biogenesis of EVs, the mechanism by which proteins and nucleic acids are selected for inclusion in EVs, and novel methods that have been employed to enhance loading of specific cargoes into EVs. As well, we discuss biodistribution of administered EVs in vivo and summarize clinical trials that have attempted to harness the therapeutic potential of EVs.

Keywords:  biodistribution; bioengineering; exosomes; extracellular vesicles; therapeutic delivery

DOI:  https://doi.org/10.1016/j.omtm.2024.101259
World J Gastroenterol. 2024 May 14. 30(18): 2391-2396

Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?

Michele Barone.

  This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology. The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.

Keywords:  Autophagy; Hepatic stellate cells; Hepatocellular carcinoma; Liver fibrosis; Renin-angiotensin system

DOI:  https://doi.org/10.3748/wjg.v30.i18.2391
Ann Gastroenterol. 2024 May-Jun;37(3):37(3): 280-290

Animal studies of sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease.

Evangelia S Makri, Eleftheria Makri, Antonis Goulas, Konstantinos Xanthopoulos, Stergios A Polyzos.

  Nonalcoholic fatty liver disease (NAFLD) is considered one of the most common chronic liver diseases. Modern lifestyle, characterized by increasing rates of obesity and type 2 diabetes mellitus (T2DM), has led to a "pandemic" of NAFLD that imposes a personal health and socioeconomic burden. Apart from overnutrition and insulin resistance, various metabolic aberrations, gut microbiota and genetic predispositions are involved in the pathogenesis of the disease. The multifactorial nature of NAFLD's pathogenesis makes the development of pharmacological therapies for patients with this disease challenging. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) are antidiabetic agents that reduce blood glucose mainly by increasing its renal excretion. As T2DM is one of the major contributors to NAFLD, SGLT-2i have emerged as promising agents for the management of NAFLD. In this review, we summarize the main animal studies on SGLT-2i in models of NAFLD.

Keywords:  Fibrosis; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; pathophysiology; sodium-glucose co-transporter 2

DOI:  https://doi.org/10.20524/aog.2024.0884
Front Cell Dev Biol. 2024 ;12 1343806

Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma.

Grigorios Papadopoulos, Eirini Giannousi, Aikaterini P Avdi, Rallia-Iliana Velliou, Polyxeni Nikolakopoulou, Antonios Chatzigeorgiou.

  Metabolic dysfunction-associated steatohepatitis (MASH) is the progressed version of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by inflammation and fibrosis, but also a pathophysiological "hub" that favors the emergence of liver malignancies. Current research efforts aim to identify risk factors, discover disease biomarkers, and aid patient stratification in the context of MASH-induced hepatocellular carcinoma (HCC), the most prevalent cancer among MASLD patients. To investigate the tumorigenic transition in MASH-induced HCC, researchers predominantly exploit preclinical animal-based MASH models and studies based on archived human biopsies and clinical trials. Recapitulating the immune response during tumor development and progression is vital to obtain mechanistic insights into MASH-induced HCC. Notably, the advanced complexity behind MASLD and MASH pathogenesis shifted the research focus towards innate immunity, a fundamental element of the hepatic immune niche that is usually altered robustly in the course of liver disease. During the last few years, however, there has been an increasing interest for deciphering the role of adaptive immunity in MASH-induced HCC, particularly regarding the functions of the various T cell populations. To effectively understand the specific role of T cells in MASH-induced HCC development, scientists should urgently fill the current knowledge gaps in this field. Pinpointing the metabolic signature, sketching the immune landscape, and characterizing the cellular interactions and dynamics of the specific T cells within the MASH-HCC liver are essential to unravel the mechanisms that adaptive immunity exploits to enable the emergence and progression of this cancer. To this end, our review aims to summarize the current state of research regarding the T cell functions linked to MASH-induced HCC.

Keywords:  T cells; adaptive immunity; hepatocellular carcinoma (HCC); immunotherapies; in vivo models; metabolic dysfunction-associated steatohepatitis (MASH); metabolic dysfunction-associated steatotic liver disease (MASLD)

DOI:  https://doi.org/10.3389/fcell.2024.1343806
Clin Exp Hepatol. 2024 Mar;10(1): 1-8

Biological rhythms of the liver.

Anatol Panasiuk, Mirosław Tarasewicz, Albert Chodowiec, Anna Łokić, Kacper Gan.

  The biological rhythm is a fundamental aspect of an organism, regulating many physiological processes. This study focuses on the analysis of the molecular basis of circadian rhythms and its impact on the functioning of the liver. The regulation of biological rhythms is carried out by the clock system, which consists of the central clock and peripheral clocks. The central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is regulated by signals received from the retinal pathway. The SCN regulates the circadian rhythm of the entire body through its indirect influence on the peripheral clocks. In turn, the peripheral clocks can maintain their own rhythm, independent of the SCN, by creating special feedback loops between transcriptional and translational factors. The main protein families involved in these processes are CLOCK, BMAL, PER and CRY. Disorders in the expression of these factors have a significant impact on the functioning of the liver. In such cases lipid metabolism, cholesterol metabolism, bile acid metabolism, alcohol metabolism, and xenobiotic detoxification can be significantly affected. Clock dysfunctions contribute to the pathogenesis of various disorders, including fatty liver disease, liver cirrhosis and different types of cancer. Therefore understanding circadian rhythm can have significant implications for the therapy of many liver diseases, as well as the development of new preventive and treatment strategies.

Keywords:  biological rhythms; circadian rhythm; liver; metabolism

DOI:  https://doi.org/10.5114/ceh.2024.136220
Biomedicines. 2024 Apr 30. pii: 992. [Epub ahead of print]12(5):

The Role of Extracellular Vesicles in Metabolic Diseases.

Carlos González-Blanco, Sarai Iglesias-Fortes, Ángela Cristina Lockwood, César Figaredo, Daniela Vitulli, Carlos Guillén.

  Extracellular vesicles represent a group of structures with the capacity to communicate with different cells and organs. This complex network of interactions can regulate multiple physiological processes in the organism. Very importantly, these processes can be altered during the appearance of different diseases including cancer, metabolic diseases, etc. In addition, these extracellular vesicles can transport different cargoes, altering the initiation of the disease, driving the progression, or even accelerating the pathogenesis. Then, we have explored the implication of these structures in different alterations such as pancreatic cancer, and in different metabolic alterations such as diabetes and its complications and non-alcoholic fatty liver disease. Finally, we have explored in more detail the communication between the liver and the pancreas. In summary, extracellular vesicles represent a very efficient system for the communication among different tissues and permit an efficient system as biomarkers of the disease, as well as being involved in the extracellular-vesicle-mediated transport of molecules, serving as a potential therapy for different diseases.

Keywords:  NAFLD; cancer; diabetes; diabetic complications; extracellular vesicles; insulin resistance; liver; miRNA; pancreas; pancreatic islets

DOI:  https://doi.org/10.3390/biomedicines12050992
Heliyon. 2024 May 15. 10(9): e30908

Pharmacological inhibition of p300 ameliorates steatosis, inflammation, and fibrosis in mice with non-alcoholic steatohepatitis.

Jung-Yeon Kim, Ah Young Yang, Kiryeong Kim, Hyun Hee Kwon, Jaechan Leem, Yun-A Kim.

  The histone acetyltransferase p300 plays a pivotal role in regulating gene expression and cellular phenotype through epigenetic mechanisms. It significantly influences lipid metabolism, which is a key factor in the pathogenesis of non-alcoholic steatohepatitis (NASH), by modulating the transcription of genes involved in lipid synthesis and accumulation. This study aimed to investigate the protective potential of inhibiting p300 in NASH. Male C57BL/6J mice were subjected to a methionine- and choline-deficient (MCD) diet for 4 weeks to induce NASH, and during this period, the p300 inhibitor C646 (10 mg/kg) was administered three times a week. C646 treatment reduced the elevation of p300 expression and histone H3 acetylation, leading to a decrease in liver injury markers in the serum and an improvement in the histological abnormalities observed in MCD diet-fed mice. C646 also reduced lipid accumulation by modulating de novo lipogenesis and suppressed inflammation, including cytokine overproduction and macrophage infiltration. Furthermore, C646 mitigated liver fibrosis and myofibroblast accumulation. This protective effect was achieved through the inhibition of apoptosis by reducing p53 and Bax expression and the suppression of ferroptosis by decreasing lipid peroxidation while enhancing antioxidant defenses. Additionally, C646 alleviated endoplasmic reticulum stress, as evidenced by the downregulation of unfolded protein response signaling molecules. These results highlight the potential of p300 as a therapeutic target for NASH.

Keywords:  Endoplasmic reticulum stress; Ferroptosis; Fibrosis; Inflammation; Non-alcoholic steatohepatitis; p300

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30908