Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity

Tilg, Herbert; Adolph, Timon E.; Dudek, Michael; Knolle, Percy

doi:10.1038/s42255-021-00501-9

Cited by 172 publications

(68 citation statements)

References 169 publications

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“…These diseases in fact can heavily impact the quantity and quality of the gut microbiota and the microbiota-dependent processing of dietary components 24 . Accordingly, increased circulating levels of TMAO have been associated with glucose intolerance, T2D, NAFLD and obesity in humans and mice 25 . It is however important to note that circulating TMAO levels have been correlated with obesity and NAFLD only in the presence of concomitant T2D, whereas this association was lost after adjusting for HOMA2-IR in patients without T2D 26 .…”

Section: Discussionmentioning

confidence: 99%

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Jomard

Liberale

Doytcheva

et al. 2022

Sci Rep

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Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg−1) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10−6 M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5–6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10−6 M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO.

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Section: Discussionmentioning

confidence: 99%

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Jomard

Liberale

Doytcheva

et al. 2022

Sci Rep

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“…Liver steatosis results in lipotoxicity that induces liver stress and injury, leading to fibrogenesis and inflammation [ 69 ]. In addition to this, dysbiosis, i.e., a disruption to the microbiota homeostasis in the gut, and dysregulated innate and adaptive immunity are crucial contributors to NAFLD progression [ 70 ]. Here, we will review the alterations in vitamin A metabolism and actions of retinoids in NAFLD with a focus on novel therapeutic approaches.…”

Section: Non-alcohol-associated Fatty Liver Diseasementioning

confidence: 99%

“…Intermittent, chronic, sterile low-grade inflammation (metaflammation) in the liver occurs in 10–30% of NAFLD patients [ 70 , 110 , 111 ]. Gut microbiome, dietary factors, and certain lipid species contribute to this metaflammation in the liver in NAFLD [ 70 ]. Both innate and adaptive immune systems are involved in this process [ 69 , 70 ].…”

Section: Non-alcohol-associated Fatty Liver Diseasementioning

confidence: 99%

“…Gut microbiome, dietary factors, and certain lipid species contribute to this metaflammation in the liver in NAFLD [ 70 ]. Both innate and adaptive immune systems are involved in this process [ 69 , 70 ]. Natural and synthetic retinoids suppress the liver’s resident macrophages’ production of inflammation mediators TNFa [ 112 ] and IL12 [ 113 ].…”

Section: Non-alcohol-associated Fatty Liver Diseasementioning

confidence: 99%

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Retinoids in the Pathogenesis and Treatment of Liver Diseases

et al. 2022

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Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases.

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“… 69 Dysregulation of liver metabolism potentially contributed to the complications observed in severe COVID‐19 patients. 66 , 68 , 70 , 71 , 72 …”

Section: Metabolic Features Of Covid‐19 Patientsmentioning

confidence: 99%

COVID‐19 metabolism: Mechanisms and therapeutic targets

Wang

Cao

Zhang³

et al. 2022

MedComm

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS‐CoV‐2‐induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID‐19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS‐CoV‐2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID‐19 metabolism. SARS‐CoV‐2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS‐CoV‐2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID‐19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS‐CoV‐2‐induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID‐19 pandemic.

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Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity

Cited by 172 publications

References 169 publications

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Retinoids in the Pathogenesis and Treatment of Liver Diseases

COVID‐19 metabolism: Mechanisms and therapeutic targets

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