Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Sandlers, Yana; Shah, Rohan; Pearce, Ryan W.; Dasarathy, Jaividhya; McCullough, Arthur J.; Dasarathy, Srinivasan

doi:10.3390/jcm9020314

Cited by 9 publications

(8 citation statements)

References 42 publications

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“…Our data from targeted quantification that showed higher plasma TCA cycle intermediary metabolites were similar to previous reports on untargeted metabolomics in patients with AH and targeted metabolomics in patients with nonalcoholic fatty liver disease. 31,46 Interestingly, we noted lower concentrations of TCA cycle intermediary metabolites in PBMC from AH compared to HC. It is not clear if these responses are mechanistically linked to mitochondrial oxidative dysfunction in PBMC in AH.…”

Section: Discussionmentioning

confidence: 67%

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Peripheral blood mononuclear cell mitochondrial dysfunction in acute alcohol‐associated hepatitis

Bellar

Attaway

Musich

et al. 2023

Clinical & Translational Med

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Background Patients with acute alcohol‐associated hepatitis (AH) have immune dysfunction. Mitochondrial function is critical for immune cell responses and regulates senescence. Clinical translational studies using complementary bioinformatics‐experimental validation of mitochondrial responses were performed in peripheral blood mononuclear cells (PBMC) from patients with AH, healthy controls (HC), and heavy drinkers without evidence of liver disease (HD). Methods Feature extraction for differentially expressed genes (DEG) in mitochondrial components and telomere regulatory pathways from single‐cell RNAseq (scRNAseq) and integrated ‘pseudobulk’ transcriptomics from PBMC from AH and HC (n = 4 each) were performed. After optimising isolation and processing protocols for functional studies in PBMC, mitochondrial oxidative responses to substrates, uncoupler, and inhibitors were quantified in independent discovery (AH n = 12; HD n = 6; HC n = 12) and validation cohorts (AH n = 10; HC n = 7). Intermediary metabolites (gas‐chromatography/mass‐spectrometry) and telomere length (real‐time PCR) were quantified in subsets of subjects (PBMC/plasma AH n = 69/59; HD n = 8/8; HC n = 14/27 for metabolites; HC n = 13; HD n = 8; AH n = 72 for telomere length). Results Mitochondrial, intermediary metabolite, and senescence‐regulatory genes were differentially expressed in PBMC from AH and HC in a cell type–specific manner at baseline and with lipopolysaccharide (LPS). Fresh PBMC isolated using the cell preparation tube generated optimum mitochondrial responses. Intact cell and maximal respiration were lower (p ≤ .05) in AH than HC/HD in the discovery and validation cohorts. In permeabilised PBMC, maximum respiration, complex I and II function were lower in AH than HC. Most tricarboxylic acid (TCA) cycle intermediates in plasma were higher while those in PBMC were lower in patients with AH than those from HC. Lower telomere length, a measure of cellular senescence, was associated with higher mortality in AH. Conclusion Patients with AH have lower mitochondrial oxidative function, higher plasma TCA cycle intermediates, with telomere shortening in nonsurvivors.

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Section: Discussionmentioning

confidence: 67%

“…Intermediary metabolites in plasma and PBMC were quantified as previously described 25,31 . Plasma for these analyses were collected from EDTA coated tubes due to dilution with Ficoll and CPT methods.…”

Section: Methodsmentioning

confidence: 99%

Peripheral blood mononuclear cell mitochondrial dysfunction in acute alcohol‐associated hepatitis

Bellar

Attaway

Musich

et al. 2023

Clinical & Translational Med

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“…Recently, studies on patients with hypothalamic-pituitary involvement after craniopharyngioma have found that the prevalence of NAFLD in children is approximately 3%–10%, while the incidence of NAFLD caused by hypothalamic-pituitary damage after craniopharyngioma has increased to approximately 50%[ 11 , 12 ]. Previously, it was generally believed that the risk factors for NAFLD were excessive fructose intake, insulin resistance, and metabolic syndrome, followed by oxidative stress injury and endoplasmic reticulum stress, adipocytokine, mitochondrial dysfunction, and bisphenol A intake[ 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

Growth hormone ameliorates hepatopulmonary syndrome and nonalcoholic steatohepatitis secondary to hypopituitarism in a child: A case report

Zhang¹,

Yuan²,

Fang³

et al. 2022

WJCC

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BACKGROUND Craniopharyngioma is a benign tumor that usually develops in children; however, it is located in the center and close to sensitive structures, such as the pituitary gland and hypothalamus. As the hypothalamus plays a crucial role in the homeostasis of anterior pituitary hormone synthesis, damage to the hypothalamus leads to multiple pituitary hormone deficiencies and non-alcoholic fatty liver disease, including hepatopulmonary syndrome (HPS). HPS has limited treatment and poor prognosis. CASE SUMMARY A girl aged 13 years and 6 mo underwent surgery for craniopharyngioma 6 years prior. Right craniotomy was performed with total resection via the corpus callosum approach, and the tumor at the base was approximately 3.5 cm × 3.5 cm × 4.0 cm. At 1 year postoperatively, she exhibited abdominal distension and weakness, and the laboratory tests revealed fatty liver disease. Thereafter, she had not visited the outpatient clinic for 2 years. Two years ago, she developed decreased activity endurance, severe cyanosis, chest tightness, wheezing, and intermittent and recurrent low fever after mild physical labor. Hepatobiliary ultrasonography, liver biopsy, and contrast echocardiography of the right heart showed cirrhosis and multiple pituitary hormone deficiencies, indicating HPS. After 1 year of treatment with recombinant human growth hormone, the liver function and oxygenation improved; she did not undergo liver transplantation. CONCLUSION Craniopharyngioma surgery can easily cause hypopituitarism, which can lead to nonalcoholic steatohepatitis and HPS in children. Early growth hormone therapy is important to improve the prognosis of these diseases.

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“…However, the role of citrate mt in the early stage of ALI remains unknown. A previous study reported that citrate concentrations were positively associated with mitochondrial dysfunction in nonalcoholic fatty liver disease 33 . Thus, it is plausible that there is a link between citrate mt and mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 89%

Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury

et al. 2022

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Necroptosis is the major cause of death in alveolar epithelial cells (AECs) during acute lung injury (ALI). Here, we report a previously unrecognized mechanism for necroptosis. We found an accumulation of mitochondrial citrate (citratemt) in lipopolysaccharide (LPS)-treated AECs because of the downregulation of Idh3α and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor–mediated inhibition of Idh3α and Slc25a1 induced citratemt accumulation and necroptosis in vitro. Mice with AEC-specific Idh3α and Slc25a1 deficiency exhibited exacerbated lung injury and AEC necroptosis. Interestingly, the overexpression of Idh3α and Slc25a1 decreased citratemt levels and rescued AECs from necroptosis. Mechanistically, citratemt accumulation induced mitochondrial fission and excessive mitophagy in AECs. Furthermore, citratemt directly interacted with FUN14 domain-containing protein 1 (FUNDC1) and promoted the interaction of FUNDC1 with dynamin-related protein 1 (DRP1), leading to excessive mitophagy-mediated necroptosis and thereby initiating and promoting ALI. Importantly, necroptosis induced by citratemt accumulation was inhibited in FUNDC1-knockout AECs. We show that citratemt accumulation is a novel target for protection against ALI involving necroptosis.

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Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Cited by 9 publications

References 42 publications

Peripheral blood mononuclear cell mitochondrial dysfunction in acute alcohol‐associated hepatitis

Peripheral blood mononuclear cell mitochondrial dysfunction in acute alcohol‐associated hepatitis

Growth hormone ameliorates hepatopulmonary syndrome and nonalcoholic steatohepatitis secondary to hypopituitarism in a child: A case report

Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury

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