Abstract:Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosylt… Show more
“…6 a, b and c) were in agreement with the above results that PD-1 restrained the Cm4 activation. The enrichments of metabolic pathways related regulons including Tfeb (24 g) [ 61 ] and Usf1 (20 g) [ 62 ] in PD-1 KO Cm4 cells were compatible with PD-1 regulating the metabolism in Cm4 cells. Fig.…”
Background
Group 2 innate lymphoid cells (ILC2s) are critical sources of type 2 cytokines and represent one of the major tissue-resident lymphoid cells in the mouse lung. However, the molecular mechanisms underlying ILC2 activation under challenges are not fully understood.
Results
Here, using single-cell transcriptomics, genetic reporters, and gene knockouts, we identify four ILC2 subsets, including two non-activation subsets and two activation subsets, in the mouse acute inflammatory lung. Of note, a distinct activation subset, marked by the transcription factor Nr4a1, paradoxically expresses both tissue-resident memory T cell (Trm), and effector/central memory T cell (Tem/Tcm) signature genes, as well as higher scores of proliferation, activation, and wound healing, all driven by its particular regulons. Furthermore, we demonstrate that the Nr4a1+ILC2s are restrained from activating by the programmed cell death protein-1 (PD-1), which negatively modulates their activation-related regulons. PD-1 deficiency places the non-activation ILC2s in a state that is prone to activation, resulting in Nr4a1+ILC2 differentiation through different activation trajectories. Loss of PD-1 also leads to the expansion of Nr4a1+ILC2s by the increase of their proliferation ability.
Conclusions
The findings show that activated ILC2s are a heterogenous population encompassing distinct subsets that have different propensities, and therefore provide an opportunity to explore PD-1's role in modulating the activity of ILC2s for disease prevention and therapy.
“…6 a, b and c) were in agreement with the above results that PD-1 restrained the Cm4 activation. The enrichments of metabolic pathways related regulons including Tfeb (24 g) [ 61 ] and Usf1 (20 g) [ 62 ] in PD-1 KO Cm4 cells were compatible with PD-1 regulating the metabolism in Cm4 cells. Fig.…”
Background
Group 2 innate lymphoid cells (ILC2s) are critical sources of type 2 cytokines and represent one of the major tissue-resident lymphoid cells in the mouse lung. However, the molecular mechanisms underlying ILC2 activation under challenges are not fully understood.
Results
Here, using single-cell transcriptomics, genetic reporters, and gene knockouts, we identify four ILC2 subsets, including two non-activation subsets and two activation subsets, in the mouse acute inflammatory lung. Of note, a distinct activation subset, marked by the transcription factor Nr4a1, paradoxically expresses both tissue-resident memory T cell (Trm), and effector/central memory T cell (Tem/Tcm) signature genes, as well as higher scores of proliferation, activation, and wound healing, all driven by its particular regulons. Furthermore, we demonstrate that the Nr4a1+ILC2s are restrained from activating by the programmed cell death protein-1 (PD-1), which negatively modulates their activation-related regulons. PD-1 deficiency places the non-activation ILC2s in a state that is prone to activation, resulting in Nr4a1+ILC2 differentiation through different activation trajectories. Loss of PD-1 also leads to the expansion of Nr4a1+ILC2s by the increase of their proliferation ability.
Conclusions
The findings show that activated ILC2s are a heterogenous population encompassing distinct subsets that have different propensities, and therefore provide an opportunity to explore PD-1's role in modulating the activity of ILC2s for disease prevention and therapy.
“…Furthermore, bile acid-induced FGF15/ 19 activates mTORC1 to phosphorylate and inhibit TFEB via a negative feedback loop. Further study suggests that in response to starvation TFEB activation also helps maintain cellular amino acid pool via activation of autophagy-lysosome proteolysis and the methionine cycle-transsulfuration pathway [37]. Taken together, new studies have revealed intriguing and complex crosstalk between bile acid metabolism and the autophagy-lysosome pathway in hepatocytes.…”
Section: Bile Acid Signaling Crosstalk With the Autophagy-lysosome Pa...mentioning
Purpose of reviewThis review aims to provide a concise update on recent advances in understanding of the bile acid metabolism and signaling in health and diseases.Recent findingsCYP2C70 has been identified as the murine cytochrome p450 enzyme that mediates the synthesis of muricholic acids to account for the major different bile acid composition between human and mice. Several studies have linked nutrient sensing bile acid signaling to the regulation of hepatic autophagy-lysosome activity, an integral pathway of the cellular adaptive response to starvation. Distinct bile acid-mediated signaling mechanisms have been shown to contribute to the complex metabolic changes post bariatric surgery, suggesting that pharmacological manipulation of the enterohepatic bile acid signaling could be a potential nonsurgical alternative to weight loss surgery.SummaryBasic and clinical studies have continued to discover novel roles of the enterohepatic bile acid signaling in regulation of key metabolic pathways. Such knowledge forms the molecular basis needed for developing safe and effective bile acid-based therapeutics for treating metabolic and inflammatory diseases.
“…While cysteine and the disulfide form cystine are relatively insoluble and toxic at high concentrations [ 80 ], cysteine is a crucial OSC and intermediate in the synthesis of proteins [ 81 ], coenzyme A [ [82] , [83] , [84] , [85] , [86] ], taurine [ [87] , [88] , [89] , [90] ], iron-sulfur clusters [ [91] , [92] , [93] ], zinc-finger complexes/metalloproteins [ 94 , 95 ], and glutathione (GSH or γ-glutamyl-cysteinyl-glycine) [ 71 , 77 , 78 , 80 , 92 , [96] , [97] , [98] , [99] , [100] , [101] , [102] ]. Intracellular cysteine is maintained in the 80–100 μM range in most tissues except in the kidney, where its concentration is only ∼1 mM [ 58 ].…”
Section: Organic Sulfur Compounds – Cysteine To Glutathione (Gsh) Coe...mentioning
confidence: 99%
“…In the mitochondria, cysteine can be oxidized to hypotaurine and taurine [ 81 , 103 , 104 ], used by cysteine desulfurase (NFS1) to generate iron–sulfur (Fe–S) clusters [ [91] , [92] , [93] ], or function in sulfhydration and persulfidation reactions [ 22 , 23 , 30 , 105 ]. In the cytosol under conditions of abundant ATP concentrations and pantothenate (B5), cysteine is combined with B5 through a series of reactions that utilize three ATP molecules to form coenzyme A [ [82] , [83] , [84] , [85] , [86] ] ( Fig. 2 ).…”
Section: Organic Sulfur Compounds – Cysteine To Glutathione (Gsh) Coe...mentioning
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