Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD

Journal of Clinical and Translational Hepatology, Год журнала: 2022, Номер 10(5), С. 939 - 946

Опубликована: Июль 6, 2022

The pathogenesis of metabolic-associated fatty liver disease (MAFLD) is complex and thought to be dependent on multiple parallel hits a background genetic susceptibility. evidence suggests that MAFLD progression dynamic two-way process relating repetitive bouts metabolic stress inflammation interspersed with endogenous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the production lipotoxins induce mitochondrial dysfunction, endoplasmic reticular stress, over reactive oxygen species (ROS). Models show marked disruption function reduced oxidative capacitance impact cellular processes including mitophagy, phosphorylation, biogenesis. excess, ROS modify insulin innate immune signaling alter expression activity essential enzymes involved in homeostasis. can also cause direct damage intracellular structures causing hepatocyte injury death. select cases, use anti-oxidants scavengers have been shown diminish pro-apoptopic effects acids. Given this link, anti-oxidant pathways target interest, Nrf2 activation showing reduction models MAFLD. Thyroid hormone receptor β (THRβ) agonists nuclear peroxisome proliferation-activated (PPAR) family gained interest reducing lipotoxicity restoring Unfortunately, true interplay between clinical molecular components remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypothesis-free analysis changes Transcriptome profiling maps unique genotype-phenotype associations various single-cell transcriptome-based projects underway, there hope novel physiological insights uncover therapeutic targets.

Язык: Английский

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Alcohol-Associated Tissue Injury: Current Views on Pathophysiological Mechanisms

Annual Review of Physiology, Год журнала: 2022, Номер 84(1), С. 87 - 112

Опубликована: Фев. 10, 2022

At-risk alcohol use is a major contributor to the global health care burden and leads preventable deaths diseases including addiction, alcoholic liver disease, cardiovascular diabetes, traumatic injuries, gastrointestinal diseases, cancers, fetal syndrome. Excessive frequent consumption has increasingly been linked alcohol-associated tissue injury pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal vitro models elucidated salient mechanisms involved alcohol-induced injury. In some cases, these pathophysiological are shared across The alcohol- metabolite–mediated include oxidative stress, inflammation immunometabolic dysregulation, gut leak dysbiosis, cell death, extracellular matrix remodeling, endoplasmic reticulum mitochondrial dysfunction, epigenomic modifications. These complex interrelated, determining interplay among them will make it possible identify how they synergistically or additively interact cause alcohol-mediated multiorgan this article, we review current understanding of

Язык: Английский

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Mitochondrial Dysfunction and Chronic Liver Disease

Current Issues in Molecular Biology, Год журнала: 2022, Номер 44(7), С. 3156 - 3165

Опубликована: Июль 9, 2022

Mitochondria are generally considered the powerhouse of cell, a small subcellular organelle that produces most cellular energy in form adenosine triphosphate (ATP). In addition, mitochondria involved various biological functions, such as biosynthesis, lipid metabolism, oxidative phosphorylation, cell signal transduction, and apoptosis. Mitochondrial dysfunction is manifested different aspects, like increased mitochondrial reactive oxygen species (ROS), DNA (mtDNA) damage, (ATP) synthesis disorder, abnormal mitophagy, well changes morphology structure. related to occurrence development chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced injury (DILI), alcoholic fatty (AFL), non-alcoholic (NAFL). this review, we summarize discuss role mechanisms disease, focusing on discussing some latest studies disease.

Язык: Английский

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Could Adverse Effects of Antibiotics Due to Their Use/Misuse Be Linked to Some Mechanisms Related to Nonalcoholic Fatty Liver Disease?

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(4), С. 1993 - 1993

Опубликована: Фев. 6, 2024

Nonalcoholic fatty liver disease, recently re-named metabolic dysfunction-associated steatotic is considered the most prevalent disease worldwide. Its molecular initiation events are multiple and not always well-defined, comprising insulin resistance, chronic low-grade inflammation, gut dysbiosis, mitochondrial dysfunction, all of them acting on genetic epigenetic grounds. Nowadays, there a growing public health threat, which antibiotic excessive use misuse. This widespread antibiotics only in humans, but also animals has led to presence residues derived foods, such as milk dairy products. Furthermore, have been used for many decades control certain bacterial diseases high-value fruit vegetables. Recently, it emphasised that antibiotic-induced changes microbial composition reduce diversity alter functional attributes microbiota. These impact human flora, setting motion chain leads straight various alterations can ultimately contribute onset progression NAFLD.

Язык: Английский

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Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis

The EMBO Journal, Год журнала: 2024, Номер 43(4), С. 507 - 532

Опубликована: Янв. 8, 2024

Abstract Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3 ) was identified to be significantly lower expressed in peripheral blood patients. In line, hepatic ACSM3 decreased mice with syndrome. Furthermore, Acsm3 knockout showed glucose lipid abnormalities, accumulation substrate lauric acid. depletion markedly function stimulated signaling via p38 MAPK pathway cascade. Consistently, mouse exhibited abnormal morphology, ATP contents, enhanced ROS levels their livers. Mechanistically, deficiency, activated nuclear receptor Hnf4α-p38 signaling. inhibitor Adezmapimod effectively rescued phenotype. Together, these findings show that disease-associated loss facilitates dysfunction a acid-HNF4a-p38 axis, suggesting novel therapeutic vulnerability systemic dysfunction.

Язык: Английский

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The signaling pathways in obesity‐related complications

Journal of Cell Communication and Signaling, Год журнала: 2024, Номер 18(2)

Опубликована: Июнь 1, 2024

Abstract Obesity, a rapidly expanding epidemic worldwide, is known to exacerbate many medical conditions, making it significant factor in multiple diseases and their associated complications. This threatening linked various harmful conditions such as type 2 diabetes mellitus, hypertension, metabolic dysfunction‐associated steatotic liver disease, polycystic ovary syndrome, cardiovascular (CVDs), dyslipidemia, cancer. The rise urbanization sedentary lifestyles creates an environment that fosters obesity, leading both psychosocial To identify individuals at risk ensure timely treatment, crucial have better understanding of the pathophysiology obesity its comorbidities. comprehensive review highlights relationship between obesity‐associated complications, including diabetes, gastrointestinal obstructive sleep apnea. It also explores potential mechanisms underlying these associations. A thorough analysis interplay complications vital developing effective therapeutic strategies combat exponential increase global rates mitigate deadly consequences this polygenic condition.

Язык: Английский

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Circulating cell-specific extracellular vesicles as biomarkers for the diagnosis and monitoring of chronic liver diseases

Cellular and Molecular Life Sciences, Год журнала: 2022, Номер 79(5)

Опубликована: Апрель 10, 2022

Abstract Chronic liver diseases represent a burgeoning health problem affecting billions of people worldwide. The insufficient performance current minimally invasive tools is recognised as significant barrier to the clinical management these conditions. Extracellular vesicles (EVs) have emerged rich source circulating biomarkers closely linked pathological processes in originating tissues. Here, we summarise contribution EVs normal function and chronic pathologies; explore use EV biomarkers, with particular focus on techniques isolate analyse cell- or tissue-specific EVs. Such approaches present novel strategy inform disease status monitor changes response treatment manner. Emerging technologies that support selective isolation analysis derived only from hepatic cells, driven recent advancements EV-based biomarker platforms for show promise bring settings.

Язык: Английский

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NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook

Antioxidants, Год журнала: 2022, Номер 11(6), С. 1131 - 1131

Опубликована: Июнь 9, 2022

Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and the most frequent complication of type 2 diabetes mellitus (T2DM). One features connecting NAFLD, T2DM cellular oxidative stress. Oxidative stress refers a redox imbalance due an inequity between capacity production elimination reactive oxygen species (ROS). major ROS sources NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce purposefully timely spatially regulated manner are crucial regulators various events metabolism, receptor signal transmission, proliferation apoptosis. contrast, dysregulated NOX-derived related onset diverse pathologies. This review provides synopsis current knowledge concerning NOX as connective elements weighs their potential relevance pharmacological targets alleviate disease.

Язык: Английский

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Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway

MedComm, Год журнала: 2023, Номер 4(2)

Опубликована: Март 14, 2023

Abstract Reticulon 3 (RTN3), an endoplasmic reticulum protein, is crucial in neurodegenerative and kidney diseases. However, the role of RTN3 liver tissues has not been described. Here, we employed public datasets, patients, several animal models to explore nonalcoholic fatty disease (NAFLD). The underlying mechanisms were studied primary hepatocytes L02 cells vitro. We found increased expression NAFLD high‐fat diet mice, oxidized low‐density lipoprotein‐treated cells. transgenic mice exhibited phenotypes lipid accumulation. Single‐cell RNA sequencing analysis indicated that might induce mitochondrial dysfunction. further showed this hepatocytes, cell line, Caenorhabditis elegans strain. Mechanistically, regulated these events through its interactions with glucose‐regulated protein 78 (GRP78), which inhibited adenosine 5 monophosphate‐activated kinase (AMPK)–isocitrate dehydrogenase 2 (IDH2) pathway. In end, knockout relieved Our study was important catabolism increase be a risk factor for steatohepatitis NAFLD.

Язык: Английский

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The role of hypoxia-inducible factor 1α in hepatic lipid metabolism

Journal of Molecular Medicine, Год журнала: 2023, Номер 101(5), С. 487 - 500

Опубликована: Март 28, 2023

Язык: Английский

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