eNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH

Sheldon, Ryan D.; Meers, Grace M.; Morris, E. Matthew; Linden, Melissa A.; Cunningham, Rory P.; Ibdah, Jamal A.; Thyfault, John P.; Laughlin, M. Harold; Rector, R. Scott

doi:10.1152/ajpendo.00096.2019

Cited by 37 publications

(43 citation statements)

References 57 publications

(70 reference statements)

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“…Using an advanced liquid chromatography tandem mass spectrometry approach, they clearly identified eNOS in their purified hepatocytes, with its highest expression in Kupffer cells and liver sinusoidal endothelial cells. Using the same methodology, our group has confirmed these findings by identifying eNOS expression in isolated primary hepatocytes from WT mice using magnetic-activated cell sorting and immunofluorescence ( Sheldon et al, 2019 ). Taken together, these more recent and methodologically robust data strongly imply the presence of eNOS in hepatocytes.…”

Section: Introductionmentioning

confidence: 82%

“…Finally, hepatic TAG accumulation was increased with 4 weeks of NOS inhibition with the non-selective NOS inhibitor (N ω -nitro-L-arginine methyl ester; L-NAME), in hyperphagic OLETF rats ( Sheldon et al, 2015 ). Moreover, we also have shown that reduced eNOS activation is associated with NAFLD progression ( Sheldon et al, 2014 , 2019 ). Importantly, loss of eNOS activation, as well as NAFLD development, were prevented with chronic voluntary wheel running exercise, indicating a potential role for exercise-induced elevations in eNOS activity in liver health ( Sheldon et al, 2014 ).…”

Section: Introductionmentioning

confidence: 83%

“…This resulted in elevated light chain 3 (LC3) II/I ratio and decreased p62 levels, indicative of increased autophagosome formation and ultimately its targeted degradation. Recent work from our lab has demonstrated hepatocellular eNOS as a novel regulator of mitochondrial homeostasis and maintaining mitophagic capacity ( Sheldon et al, 2019 ). Hepatic mitochondria from eNOS null mice displayed decreased markers of mitochondrial biogenesis (PGC1α, TFAM) and autophagy/mitophagy (BNIP3, LC3II/I).…”

Section: The Role Of Enos In Mitochondrial Dynamics and Functionmentioning

confidence: 99%

“…Genetic ablation of eNOS in mice, as well as small interfering RNA (siRNA) knockdown (KD) of eNOS in isolated primary hepatocytes result in hepatocytes lacking eNOS. This leads to a reduction in markers of hepatic mitochondrial biogenesis [PPARγ coactivator-1α (PGC-1 α), mitochondrial transcription factor A (TFAM)], and also markers of autophagy/mitophagy [BCL-2-interacting protein-3 (BNIP3), 1A/1B light chain 3B (LC3)], and decreased fatty acid oxidation in primary hepatocytes [as measured by complete 14 Co 2 production ( Sheldon et al, 2019 )]. Whether this process is governed by a reduction in nitric oxide (NO) is yet to be determined.…”

Section: The Role Of Enos In Mitochondrial Dynamics and Functionmentioning

confidence: 99%

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The Emerging Role of Hepatocellular eNOS in Non-alcoholic Fatty Liver Disease Development

2020

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Non-alcoholic fatty liver disease (NAFLD) is comprised of a spectrum of liver injury ranging from excess fat accumulation in the liver (steatosis), to steatohepatitis (NASH), to its end stage of cirrhosis. A hallmark of NAFLD progression is the decline in function of hepatic mitochondria, although the mechanisms remain unresolved. Given the important role endothelial nitric oxide synthase (eNOS) plays in mitochondrial dynamics in other tissues, it has emerged as a potential mediator of maintaining mitochondrial function in the liver. In this mini review, we summarize the most relevant findings that extends current understanding of eNOS as a regulator of mitochondrial biogenesis, and identifies a potential additional role in mitochondrial turnover and attenuating inflammation during NAFLD development and progression.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 83%

Section: The Role Of Enos In Mitochondrial Dynamics and Functionmentioning

confidence: 99%

Section: The Role Of Enos In Mitochondrial Dynamics and Functionmentioning

confidence: 99%

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The Emerging Role of Hepatocellular eNOS in Non-alcoholic Fatty Liver Disease Development

2020

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“…The mitochondrial quality control (MQC) mechanism involves intricate regulation of several processes such as proteostasis, biogenesis, dynamics, and mitophagy, all of which are integral to maintaining cellular homeostasis as shown in Figure 2 [5][6][7]. The failure of the quality control processes results in mitochondrial dysfunction and is one of the underlying causes for NAFLD [8]. MQC involves coordinated regulation of a hierarchical network of pathways that act sequentially from an individual protein molecule to the whole organelle [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.

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

et al. 2022

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Background and Aims NAFLD and its more‐advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver‐related, and all‐cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant. Approach and Results To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline‐NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite‐NASH (D‐NASH; steatosis, lobular inflammation, and hepatocellular ballooning). Hepatic mitochondrial complete FAO to CO2 and the rate‐limiting enzyme in β‐oxidation (β‐hydroxyacyl‐CoA dehydrogenase activity) were reduced by ~40%–50% with D‐NASH compared with CTRL. This corresponded with increased hepatic mitochondrial reactive oxygen species production, as well as dramatic reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission, and fusion in NAFL and NASH. Conclusions These findings suggest that compromised hepatic FAO and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity.

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eNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH

Cited by 37 publications

References 57 publications

The Emerging Role of Hepatocellular eNOS in Non-alcoholic Fatty Liver Disease Development

The Emerging Role of Hepatocellular eNOS in Non-alcoholic Fatty Liver Disease Development

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

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

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