Evidence showing lipotoxicity worsens outcomes in covid-19 patients and insights about the underlying mechanisms

Cartin‐Ceba, Rodrigo; Khatua, Biswajit; El-Kurdi, Bara; Trivedi, Shubham; Kostenko, Sergiy; Imam, Zaid; Smith, Ryan J.; Snozek, Christine L.H.; Navina, Sarah; Sharma, Vijeta; McFayden, Bryce; Ionescu, Filip; Stolow, Eugene; Keiser, Sylvia; Tejani, Aziz; Harrington, Allison; Acosta, Phillip; Kuwelker, Saatchi; Echavarria, Juan; Nair, Girish B.; Bataineh, Adam; Singh, Vijay

doi:10.1016/j.isci.2022.104322

Cited by 18 publications

(18 citation statements)

References 85 publications

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“…The physiological concentrations of unsaturated fatty acids linoleic or arachidonic acid impaired the binding of VD to VDBP ( 47 ), which might be one of the manifestations of unsaturated fatty acid lipid toxicity. The unbound fatty acids, such as linoleic acid, reacted with Alb and induced hypoalbuminemia ( 48 ). Therefore, the upregulation of VDBP, Alb, and Afm in the RSGB treatment group also contributed to the reduction of lipotoxicity.…”

Section: Discussionmentioning

confidence: 99%

The anti-aging effects of Renshen Guben on thyrotoxicosis mice: Improving immunosenescence, hypoproteinemia, lipotoxicity, and intestinal flora

Feng

Li²,

Xia³

et al. 2022

Front. Immunol.

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With the rapid aging of the population, the control of age-related disease susceptibility and prognosis faces greater challenges. There is an urgent need for a strategy to maintain the vitality of elderly people. In this study, the effect of Renshen Guben (RSGB) oral liquid was investigated on an accelerated aging mice model of thyrotoxicosis by conventional detection methods combined with multiomics technology. The results showed that RSGB increased the number of neutrophils and lymphocytes, enhanced the function of lymphocytes, and increased the levels of complement and antimicrobial peptides, which indicated that RSGB improved the immunity of thyrotoxicosis mice at the cellular and molecular levels. RSGB corrected malnutrition in thyrotoxicosis mice by improving anemia, hypoalbuminemia, ion transporters, and vitamin-binding proteins. RSGB significantly reduced the lipotoxicity by reducing the level of fatty acids, triglyceride, sphingolipids, and glucocorticoids, thus increasing the level of docosapentaenoic acid (DPA) and bile acids, which contributed to improve immunosenescence. The intestinal defense ability of thyrotoxicosis mice was enhanced with the increase of bile acids and lactic acid bacteria by the RSGB treatment. The plant metabolomics analysis showed that there were various active components in RSGB oral liquid and medicated serum, including terpenoids, phenolic acids, flavonoids, tannin, alkaloids, organic acids, phenolamines, amino acids, and others. They have antioxidant, immune regulation, and anti-aging effects, which was the material basis of RSGB. Totally, RSGB protected the thyrotoxicosis mice against aging by improving immunosenescence, hypoproteinemia, lipotoxicity, and the intestinal flora. It will be beneficial for improving the disease susceptibility and prognosis of the elderly.

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Section: Discussionmentioning

confidence: 99%

The anti-aging effects of Renshen Guben on thyrotoxicosis mice: Improving immunosenescence, hypoproteinemia, lipotoxicity, and intestinal flora

Feng

Li²,

Xia³

et al. 2022

Front. Immunol.

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“…The release of DAMPs to extracellular spaces is a characteristic of necrosis that distinguishes it from apoptosis 58 . Several previous studies have also reported that circulating levels of DAMPs, such as HMGB-1 [59][60][61][62] , histone 62,63 , cell free-DNA 62,63 , mitochondrial DNA [64][65][66] and S100 proteins 67,68 are elevated in severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

Tojo

Yamamoto

Tamada

et al. 2022

Preprint

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Rationale: Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after passing the peak of viral load. However, the underlying mechanisms remain unclear. Objectives : Here, we assess whether alveolar epithelial cell necrosis and subsequent releases of damage associated molecular patterns (DAMPs) at an early disease stage aggravate ARDS with COVID-19 Methods: In patients with COVID-19 with and without ARDS and healthy adults, serum levels of the following were quantified: an epithelial total cell death marker, cytokeratin18-M65; an epithelial apoptosis marker, CK18-M30; HMGB-1; and alveolar epithelial and endothelial injury markers, sRAGE, angiopoietin-2, and surfactant protein-D. Molecular mechanisms of alveolar epithelial cell death and effects of HMGB-1 neutralization on alveolar tissue injury were assessed using a mouse model of COVID-19-induced ARDS. Measurements and main results: The levels of CK18-M65, CK18-M30, and alveolar tissue injury markers were elevated in early stages of ARDS. The median M30/M65 ratio, an epithelial apoptosis indicator, was 31.50% in patients with ARDS, a value significantly lower than that of non-ARDS patients or healthy subjects. Serum levels of HMGB-1, one of DAMPs released from necrotic cells, were also significantly elevated in ARDS versus non-ARDS patients. In a COVID-19-induced ARDS mouse model, alveolar epithelial cell necrosis involved two forms of programmed necrosis, necroptosis and pyroptosis. Finally, neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Conclusions: Necrosis, including necroptosis and pyroptosis, seems to be the primary form of alveolar epithelial cell death, and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

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“…Cytokines, including interleukin-6 (IL-6), [143][144][145][146] monocyte chemoattractant protein-1 (MCP-1), 147 and tumor necrosis factor α (TNF-α), 144 along with adipokines, including resistin and visfatin, 148,149 are elevated during clinical AP and may correlate with disease severity [143][144][145][146][147][150][151][152] or organ failure. 23 Recent studies have shown that such a cytokine response may follow the generation 129,132,137 or administration of FAs 129,131,153 that are released in severe AP. The evidence supporting hydrolysis of TGs to FAs in causing the cytokine response initially came from genetically obese mice with pancreatitis induced by IL-12 and IL-18 injection, which had marked increases in serum IL-6, MCP-1, and TNF-α and unsaturated FA concentrations, all of which were decreased by lipase inhibition.…”

Section: Effects Of Fas On the Inflammatory Responsementioning

confidence: 99%

“…Specifically, a reduction in the activities of mitochondrial complexes I and V was noted with the unsaturated FA LA (C18:2) although not with pamitic acid (C16:0). 130 Recent live imaging studies using fluorescent LA show that its uptake into cells results in mitochondrial depolarization 153 both of which can be rapidly reversed by extracellular albumin. 131,153,162 The pathophysiological relevance of this mitochondrial dysfunction in AP was supported by electron microscopy demonstrating lamellar inclusions and injury in obese mice developing organ failure from increased FA levels.…”

Section: Effects Of Fas On the Inflammatory Responsementioning

confidence: 99%

Mechanisms linking hypertriglyceridemia to acute pancreatitis

et al. 2023

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Hypertriglyceridemia (HTG) is a metabolic disorder, defined when serum or plasma triglyceride concentration (seTG) is >1.7 mM. HTG can be categorized as mild to very severe groups based on the seTG value. The risk of acute pancreatitis (AP), a serious disease with high mortality and without specific therapy, increases with the degree of HTG. Furthermore, even mild or moderate HTG aggravates AP initiated by other important etiological factors, including alcohol or bile stone. This review briefly summarizes the pathophysiology of HTG, the epidemiology of HTG‐induced AP and the clinically observed effects of HTG on the outcomes of AP. Our main focus is to discuss the pathophysiological mechanisms linking HTG to AP. HTG is accompanied by an increased serum fatty acid (FA) concentration, and experimental results have demonstrated that these FAs have the most prominent role in causing the consequences of HTG during AP. FAs inhibit mitochondrial complexes in pancreatic acinar cells, induce pathological elevation of intracellular Ca2+ concentration, cytokine release and tissue injury, and reduce the function of pancreatic ducts. Furthermore, high FA concentrations can induce respiratory, kidney, and cardiovascular failure in AP. All these effects may contribute to the observed increased AP severity and frequent organ failure in patients. Importantly, experimental results suggest that the reduction of FA production by lipase inhibitors can open up new therapeutic options of AP. Overall, investigating the pathophysiology of HTG‐induced AP or AP in the presence of HTG and determining possible treatments are needed.

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Evidence showing lipotoxicity worsens outcomes in covid-19 patients and insights about the underlying mechanisms

Cited by 18 publications

References 85 publications

The anti-aging effects of Renshen Guben on thyrotoxicosis mice: Improving immunosenescence, hypoproteinemia, lipotoxicity, and intestinal flora

The anti-aging effects of Renshen Guben on thyrotoxicosis mice: Improving immunosenescence, hypoproteinemia, lipotoxicity, and intestinal flora

Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

Mechanisms linking hypertriglyceridemia to acute pancreatitis

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