The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Pathogenesis

Venkatesan, Nanditha; Doskey, Luke C.; Malhi, Harmeet

doi:10.1016/j.ajpath.2023.08.007

Cited by 8 publications

(6 citation statements)

References 96 publications

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“…According to the so-called “lipotoxicity theory”, the occurrence of hepatocellular injury and lobular inflammation—which distinguish NASH from uncomplicated steatosis (NAFL)—can result from the chemical types of fatty substrates accumulated and how they are stored in intrahepatic lipid droplets (a phenomenon that is under control of genetic polymorphisms, such as the PNPLA3 I148M variant) rather than from the extent of intrahepatic fat accumulation [ 101 ]. The lipotoxicity theory highlights the possibility that, while triglycerides are chemically inert and do not have the property to damage the hepatocytes, other lipid substrates may trigger more complex and dangerous biological events, such as mitochondrial injury and endoplasmic reticulum (ER) stress, eventually culminating in activation of c-Jun N-terminal kinase (JNK) and release of danger-associated molecular patterns (DAMPs), apoptosis, necroptosis, pyroptosis, or autophagy [ 101 , 102 , 103 ].…”

Section: Nash As a Metabolic Disorder: Epidemiology And Mechanismsmentioning

confidence: 99%

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Lonardo,

Ballestri,

Mantovani

et al. 2024

Metabolites

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This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

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Section: Nash As a Metabolic Disorder: Epidemiology And Mechanismsmentioning

confidence: 99%

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Lonardo,

Ballestri,

Mantovani

et al. 2024

Metabolites

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“…Studies have shown that ceramide-induced ER stress plays an important role in the mechanism of glucolipotoxicity-induced β-cell dysfunction ( Liu et al, 2023 ). The de novo ceramide synthesis initiates in the cytoplasmic leaflet of the ER membrane, and ceramide plays a key role in regulating membrane thickness and stability ( Venkatesan et al, 2023 ). Ceramide accumulation induces ER stress by increasing protein misfolding and aggregation, and perturbs calcium signaling in the ER ( Boslem et al, 2013 ; Chen et al, 2023 ).…”

Section: Abnormal Ceramide Metabolism Leads To the Pathogenesis Of T2dmmentioning

confidence: 99%

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Pan,

Li,

Lin

et al. 2024

Front. Pharmacol.

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The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.

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“…Предложенный подход основывался на том факте, что NAFLD является главным образом следствием системной метаболической дисфункции, в частности наличия МС [1,3,[18][19][20][21]. Другим обстоятельством, которое необходимо учитывать при обсуждении данной нозологии, представляется многофакторность этиопатогенеза, который включает особенности питания и потребления алкоголя, нарушение целостности кишечного барьера и особенности микробиоты кишечника, дисфункцию субклеточных структур (митохондрий, эндоплазматического ретикулума), а также нарушение обмена веществ и/или гормональные расстройства [20,[22][23][24][25][26][27]. Выдвинуты предложения по изменению термина NAFLD с заменой определения «неалкогольная» на один из вариантов, указывающих на основной вклад в поражение печени одного из перечисленных факторов патогенеза [28,29].…”

Section: эволюция номенклатурыunclassified

The clinician's view on the advantages and contradictions of the new nomenclature of steatotic liver disease: A review

Pavlov,

Teplyuk,

Lazebnik

et al. 2024

Terapevticheskii arkhiv

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In September 2023, the European Association for the Study of the Liver (EASL) updated the disease nomenclature for non-alcoholic (metabolically associated) fatty liver disease. The goals of the revision were to increase awareness among health care professionals, civil society and patients about the disease, its course, treatment and outcomes; combating stigma; focusing on the initial etiological factor, including the main (cardiometabolic) risk of disease progression; improved diagnosis based on disease biomarkers; positive impact on the potency to search for new drugs; the ability to provide personalized medical care. The terms “non-alcoholic” and “fatty” were considered stigmatizing, and therefore, it was proposed to use the term steatotic liver disease (SLD) as the name of this nosology. The terms non-alcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) have been replaced by the term metabolic dysfunction-associated steatotic liver disease (MASLD). In the case of being combined with an alcohol factor, a diagnosis in which metabolic dysfunction is combined with alcoholic liver disease is referred to as MetALD. The fundamental principle in the diagnosis of MASLD is the presence of at least one of the cardiometabolic risk factors. Alcohol consumption interacts with cardiometabolic risk factors and increases the risk of SLD decompensation. The term nonalcoholic steatohepatitis (NASH), according to the new nomenclature, has been replaced by the term metabolic dysfunction-associated steatohepatitis (MASH). The adoption of the new nomenclature should help to increase awareness about the disease, its course and outcomes, as well as improve the quality of diagnosis and treatment.

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The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Pathogenesis

Cited by 8 publications

References 96 publications

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

The clinician's view on the advantages and contradictions of the new nomenclature of steatotic liver disease: A review

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