Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease

Meroni, Marica; Longo, Miriam; Dongiovanni, Paola

doi:10.37349/emed.2020.00015

Cited by 5 publications

(10 citation statements)

References 208 publications

(277 reference statements)

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“…A common SNP (C47T, rs4880) determines a single amino acid (Ala16Val) replacement in the signaling sequence of the enzyme, reducing its function in the mitochondrial matrix. In this way, MnSOD can influence the genetic susceptibility to NASH, due to a lack of cell detoxification from the superoxide anion and an increased hepatocellular exposure to oxidative damage [356,357]. Evidence of the relationship between C47T SNP and NAFLD evolution came from a study that demonstrated how the increase in mitochondrial OS, resulting from this genetic predisposition, increases the fibrosis stage and, therefore, is associated with a more advanced NAFLD [358].…”

Section: Single Nucleotide Polymorphismsmentioning

confidence: 99%

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Smirne

Croce

Benedetto

et al. 2022

Livers

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Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.

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Section: Single Nucleotide Polymorphismsmentioning

confidence: 99%

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Smirne

Croce

Benedetto

et al. 2022

Livers

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“…Familial, twin, and epidemiological studies indicated that NAFLD has a strong heritable component, which contributes to the huge inter-individual phenotypic variability. Dongiovanni et al demonstrated that hepatic fat accumulation represents the main driver of the progression to the end-stage of liver damage in genetically predisposed individuals, and recently proposed a detailed review including all the candidate genes related to NAFLD susceptibility [ 195 , 196 ].…”

Section: The Link Among Nafld Mitochondrial Dysfunction and Hcc: The Relevance Of Geneticsmentioning

confidence: 99%

“…PNPLA3 is mainly localized on the ER and LDs surface in hepatocytes, adipocytes and HSCs, and it may be transcriptionally induced or post-translationally modified to provide TG hydrolysis during the post-prandial or hyper-insulinemic state. Patients carrying the G allele lost PNPLA3 enzymatic activity, which impedes TG disposal and interferes with the activity of other lipases, such as PNPLA2 [ 196 , 197 ]. Beyond the triacylglycerol remodeling, PNPLA3 exerts widespread effects on human liver metabolome [ 198 ], influencing mitochondrial functions, glucose reprogramming and tumorigenesis.…”

Section: The Link Among Nafld Mitochondrial Dysfunction and Hcc: The Relevance Of Geneticsmentioning

confidence: 99%

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Longo

Paolini

Meroni

et al. 2021

IJMS

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic–lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.

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“…HEY1 transcriptionally represses PINK1 in Huh7, reduced mitochondrial mass and altered inner cristae morphology [171]. review including all the candidate genes related to NAFLD susceptibility [199,200].…”

Section: The Impact Of Hypoxia On Hepatic Metabolic Reprogramming Andmentioning

confidence: 99%

“…PNPLA3 mainly localized on ER and LDs surface in hepatocytes, adipocytes and HSCs and it may be transcriptionally induced or post-translationally modified to provide TG hydrolysis during post-prandial or hyperinsulinemic state. Patients carrying the G allele lost PNPLA3 enzymatic activity, which impedes TG disposal and interferes with the activity of other lipases as PNPLA2 [200,201]. Beyond the triacylglycerol remodelling, PNPLA3 exerts widespread effects on human liver metabolome [202], influencing mitochondrial functions, glucose reprogramming and tumorigenesis.…”

Section: The Impact Of Hypoxia On Hepatic Metabolic Reprogramming Andmentioning

confidence: 99%

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Longo¹,

Paolini²,

Meroni³

et al. 2021

Preprint

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles which may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlighted that mitochondrial dysfunction due to loss of mitochondrial flexibility, may arise before overt NAFLD and since the early stages of liver injury. Mitochondrial failure not only promotes hepatocellular damage, but also release signals (mito-DAMPs) which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by remodeling of glucidic-lipidic metabolism combined to reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research purposes and for development of potential preventive or curative strategies.

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Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver disease

Cited by 5 publications

References 208 publications

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

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