Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research

Berardo, Clarissa; Pasqua, Laura Giuseppina Di; Cagna, Marta; Richelmi, Plinio; Vairetti, Mariapia; Ferrigno, Andrea

doi:10.3390/ijms21249646

Cited by 44 publications

(35 citation statements)

References 207 publications

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“…In the process of counteracting the increase in oxidative stress, energy and amino acids are consumed resulting in the restoration of normal ROS level. Alternatively, in case of prolonged increase in ROS production, the instauration of a chronic condition may lead to various pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, cancer and non-alcoholic steatohepatitis [27,28].…”

Section: Direct Antioxidant Activitymentioning

confidence: 99%

Changes in Glutathione Content in Liver Diseases: An Update

et al. 2021

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Glutathione (GSH), a tripeptide particularly concentrated in the liver, is the most important thiol reducing agent involved in the modulation of redox processes. It has also been demonstrated that GSH cannot be considered only as a mere free radical scavenger but that it takes part in the network governing the choice between survival, necrosis and apoptosis as well as in altering the function of signal transduction and transcription factor molecules. The purpose of the present review is to provide an overview on the molecular biology of the GSH system; therefore, GSH synthesis, metabolism and regulation will be reviewed. The multiple GSH functions will be described, as well as the importance of GSH compartmentalization into distinct subcellular pools and inter-organ transfer. Furthermore, we will highlight the close relationship existing between GSH content and the pathogenesis of liver disease, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), chronic cholestatic injury, ischemia/reperfusion damage, hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatocellular carcinoma. Finally, the potential therapeutic benefits of GSH and GSH-related medications, will be described for each liver disorder taken into account.

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Section: Direct Antioxidant Activitymentioning

confidence: 99%

Changes in Glutathione Content in Liver Diseases: An Update

et al. 2021

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“…Metabolic associated fatty liver disease (MAFLD), previously referred to as nonalcohol fatty liver disease (NAFLD), 1 is the most common cause of chronic liver disease worldwide and can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma 2‐4 . It is a clinicopathological syndrome characterized by the lipid deposition in hepatocytes in patients without a history of excessive alcohol intake 5,6 . The global prevalence of MAFLD is 25.2%, with the highest prevalence rates occurring in the Middle East and South America and the lowest in Africa 7 .…”

Section: Introductionmentioning

confidence: 99%

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

Huang

Chen

et al. 2021

Liver International

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Aim The aim of this study is to investigate the effect of maternal nicotine exposure (MNE) on the development of metabolic associated fatty liver disease (MAFLD) in adulthood offspring and the underlying mechanism. Methods Pregnant mice (n = 22) were subcutaneously injected with either saline vehicle (n = 11) or nicotine (n = 11) twice a day on gestational days 11‐21. Offspring mice (n = 176) from both groups were weaned at postnatal day 21, and for 6 months after postnatal day 21, 96 mice were fed either a standard chow diet (n = 48) or a high‐fat diet (n = 48). Serum lipid indicators, liver function indicators, insulin, and liver mitochondrial respiration were analyzed. The expression levels of fibrosis‐related proteins, phosphorylated PI3K, phosphorylated Akt, sterol regulatory element‐binding transcription factor 1 (SREBP1c), and peroxisome proliferator‐activated receptor alpha (PPAR‐α) were detected in the liver by immunohistochemistry and Western blotting. Results MNE significantly decreased the weight of both maternal and offspring mice (~30%) and inhibited organ growth in offspring mice (P < .05). MNE also significantly increased serum levels of total bile acid, triglycerides, total cholesterol, glucose, alanine aminotransferase, aspartate aminotransferase, low‐density lipoprotein, and insulin while decreasing serum high‐density lipoprotein levels and mitochondrial respiration activity in mice fed either the normal diet or high‐fat diet (all P < .05). These effects of MNE on lipid metabolism and insulin resistance were mediated via PI3K and Akt phosphorylation and down‐regulation of SREBP1c and PPAR‐α. Conclusion Our data indicate MNE induces lipid metabolism disorder and insulin resistance to promote MAFLD progression in adult offspring through activation of PI3K/Akt signaling and suppression of SREBP1c and PPARα protein expression.

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“…De novo lipogenesis and fatty acid oxidation are implicated in NAFLD pathogenesis, although lipid uptake, storage and export also play a role [ 126 , 127 ]. Fatty acid oxidation is a cyclic process in which fatty acids are shortened, releasing acetyl-CoA after each cycle [ 128 , 129 ]. One of the main regulators of this process is the peroxisome proliferator-activated receptor-α (PPARα) [ 130 ], However, other factors are also involved in fine-tuning the process.…”

Section: Cyp2e1 In Nafldmentioning

confidence: 99%

CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload

Harjumäki

Pridgeon

Ingelman‐Sundberg

2021

IJMS

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CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.

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Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research

Cited by 44 publications

References 207 publications

Changes in Glutathione Content in Liver Diseases: An Update

Changes in Glutathione Content in Liver Diseases: An Update

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload

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