Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD

Moore, Mary P.; Cunningham, Rory P.; Meers, Grace M.; Johnson, Sarah A.; Wheeler, Andrew A.; Ganga, Rama; Spencer, Nicole; Pitt, J. Benjamin; Diaz-Arias, Alberto A.; Swi, Ahmed; Hammoud, Ghassan M.; Ibdah, Jamal A.; Parks, Elizabeth J.; Rector, R. Scott

doi:10.1002/hep.32324

Cited by 122 publications

(113 citation statements)

References 61 publications

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“…The results of this study showed that hepatic mitochondrial complete FAO was reduced by ~40-50% in subjects with NASH compared to the control subjects with normal histology. This decrease corresponded with increased hepatic mitochondrial reactive oxygen species production and reductions in the markers of mitochondrial biogenesis and mitophagy [131]. These findings support a link between mitochondrial dysfunction and NAFLD/NASH in humans and suggest that impaired hepatic fatty acid oxidation and reduced mitochondrial quality are strongly linked to increasing NAFLD severity in patients with obesity.…”

Section: Fao and Nafldsupporting

confidence: 62%

“…More recently, our group has investigated the relationship between NAFLD/NASH, mitochondrial fatty acid oxidation in liver, and hepatic mitochondrial quality in human subjects [131]. We obtained liver biopsies from patients with obesity undergoing bariatric surgery and correlated the liver histology to the mitochondrial fatty acid oxidation measured in the liver tissue.…”

Section: Fao and Nafldmentioning

confidence: 99%

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Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease

Ramanathan

Ali

Ibdah

2022

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world’s population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH.

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Section: Fao and Nafldsupporting

confidence: 62%

Section: Fao and Nafldmentioning

confidence: 99%

Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease

Ramanathan

Ali

Ibdah

2022

IJMS

Self Cite

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“…Deficient ETC functioning would render hepatocytes more susceptible to oxidative damage upon FFA excessive arrival, thus sustaining a vicious circle between hampered FA oxidative capacity and increased ROS production [ 123 , 227 ]. In line with the results of preclinical investigations, studies indicate that mitochondrial redox balance, appropriate FA oxidation and ETC capacity are important components defense mechanisms against NAFLD in humans [ 228 , 229 ].…”

Section: Oxidative Stress In Nafldmentioning

confidence: 84%

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

Nascè¹,

Gariani

Jornayvaz

et al. 2022

Antioxidants

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

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“…In addition, mitophagy plays a role activating of the inflammasome [ 106 ]. Moore et al have recently linked compromised mitochondria to increasing NAFLD severity in patients with obesity [ 141 ]. They reported a 40–50% reduction in β-oxidation in NASH patients, associated with increased hepatic ROS production and a reduction in markers of mitochondrial biogenesis, autophagy, mitophagy, fission, and fusion [ 141 ].…”

Section: Pathogenesis Of Nafldmentioning

confidence: 99%

NAFLD: Mechanisms, Treatments, and Biomarkers

Nassir

2022

Biomolecules

161

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Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments.

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Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD

Cited by 122 publications

References 61 publications

Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease

Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease

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

NAFLD: Mechanisms, Treatments, and Biomarkers

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