TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism

Shepard, Christopher R.

doi:10.3389/fendo.2020.613639

Cited by 30 publications

(24 citation statements)

References 252 publications

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“…The mitochondrial GSH depletion is also induced by cholesterol accumulation in the progression of SS to NASH [115]. Mitochondrial DNA (mtDNA) released from fatty liver-damaged hepatocytes then causes liver inflammation by TRL-9 activation [116] and its levels tend to decrease in patients with more advanced forms of NAFLD [117]. Thus, increased OS triggers hepatic stress pathways; therefore, maintaining cellular redox homeostasis is a promising strategy for NASH therapy [118].…”

Section: Evidences On the Role Of Oxidative Stress On Nafld Progressionmentioning

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: Evidences On the Role Of Oxidative Stress On Nafld Progressionmentioning

confidence: 99%

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Smirne

Croce

Benedetto

et al. 2022

Livers

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“…34 TLR9 is an intracellular nucleic acid-sensing pattern recognition receptor, and its over-activation by elevated circulating level of mitochondrial DNA in NAFLD patients has been deemed as a driver of NAFLD progression. 47 Notably, TLR9 expression of circulating CD8 + T cells in healthy volunteers also appeared to be higher than NAFL patients at a comparable level to NASH patients 34 , indicating the need of establishing NAFLD diagnosis before future utilization of this marker.…”

Section: Changes In Association With Nashmentioning

confidence: 97%

Peripheral immune cells in NAFLD patients: A spyhole to disease progression

Lin

Fan

2022

eBioMedicine

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Nonalcoholic fatty liver disease (NAFLD) is a worldwide leading cause of chronic liver disease, but we still lack ideal non-invasive tools for diagnosis and evaluation of nonalcoholic steatohepatitis (NASH) and related liver fibrosis in NAFLD population. Systemic immune dysregulations such as metabolic inflammation are believed to play central role in the development of NAFLD, signifying the hope of utilizing quantitative and phenotypic changes in peripheral immune cells among NAFLD patients as a diagnostic tool of NASH and fibrosis. In this review, we summarize the known changes in peripheral immune cells from NAFLD/NASH patients and their potential relationship with NAFLD and NASH progression. Potential challenges and possible solutions for further clinical translation are also discussed.

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“…TLR9 is the most common recognition receptor of mtDNA. TLR9 is primarily expressed in macrophages, dendritic cells and B lymphocytes, and recognizes the DNA CpG motif in bacteria and viruses ( 42 ). Similar to bacterial DNA, mtDNA is hypomethylated on the CpG motif ( 43 ), making it a potent activator of TLR9.…”

Section: Effect Of Mtdna On the Occurrence And Development Of Sirsmentioning

confidence: 99%

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Kong

Song

2022

Mol Med Rep

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Mitochondria are key organelles of cellular energy metabolism; both mitochondrial function and metabolism determine the physiological function of cells and serve an essential role in immune responses. Key damage-associated molecular patterns (daMPs), such as mitochondrial dna and n-formyl peptides, released following severe trauma-induced mitochondrial damage may affect the respiratory chain, enhance oxidative stress and activate systemic inflammatory responses via a variety of inflammation-associated signaling pathways. Severe trauma can lead to sepsis, multiple organ dysfunction syndrome and death. The present review aimed to summarize the pathophysiological mechanisms underlying the effects of human mitochondrial injury-released daMPs on triggering systemic inflammatory responses and to determine their potential future clinical applications in preventing and treating sepsis. Contents1. introduction 2. Structure and function of mitochondria 3. mtdaMPs 4. mtdna 5. effect of mtdna on the occurrence and development of SirS 6. nFPs 7. TFaM 8. mtdaMPs and intestinal barrier dysfunction 9. conclusion can

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TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism

Cited by 30 publications

References 252 publications

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Peripheral immune cells in NAFLD patients: A spyhole to disease progression

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

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