NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are ...decreased in patients with NASH, but the roles of membrane PC composition in the pathogenesis of NASH have not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver.
The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver-specific knockout (LKO) mice. RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We showed that LPCAT3 was dramatically suppressed in human NASH livers, and its expression was inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpression of Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH.
These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.
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BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Plasmalogens are a class of phospholipids containing vinyl ether linked aliphatic groups at the sn-1 position. Plasmalogens are known to contain 16- and 18-carbon aliphatic groups at the sn-1 ...position. Here, we reveal that the human neutrophil plasmenylethanolamine pool uniquely includes molecular species with very long carbon chain (VLC) aliphatic groups, including 20-, 22- and 24-carbon vinyl ether linked aliphatic groups at the sn-1 position. We identified these novel VLC plasmalogen species by electrospray ionization mass spectrometry methods. VLC plasmalogens were only found in the neutrophil plasmenylethanolamine pool. During neutrophil activation, VLC plasmenylethanolamines undergo myeloperoxidase-dependent oxidation to produce VLC 2-chlorofatty aldehyde and its oxidation product, 2-chlorofatty acid (2-ClFA). Furthermore, plasma concentrations of VLC 2-ClFA are elevated in human sepsis. These studies demonstrate for the first time VLC plasmenylethanolamine molecular species, their myeloperoxidase-mediated chlorolipid products and the presence of these chlorolipids in human sepsis.
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•Novel very long chain (VLC) plasmenylethanolamine molecular species are discovered in human neutrophils.•VLC plasmenylethanolamines undergo myeloperoxidase dependent oxidation to produce new VLC chlorinated lipids.•VLC 2-chlorofatty acids are elevated in human sepsis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ...ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein.
A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO mice, and in their liver, adipose tissue, and serum. Lipidomics and RNA-Seq studies were performed in the liver samples of HFD-fed WT and UKO mice. Proteomic studies were conducted to identify Ube4A's targets in metabolism. Furthermore, a mechanism by which Ube4A regulates metabolism was identified.
Although the body weight and composition of young, chow-fed WT and UKO mice are similar, the knockouts exhibit mild hyperinsulinemia and insulin resistance. HFD feeding substantially augments obesity, hyperinsulinemia, and insulin resistance in both sexes of UKO mice. HFD-fed white and brown adipose tissue depots of UKO mice have increased insulin resistance and inflammation and reduced energy metabolism. Moreover, Ube4A deletion exacerbates hepatic steatosis, inflammation, and liver injury in HFD-fed mice with increased lipid uptake and lipogenesis in hepatocytes. Acute insulin treatment resulted in impaired activation of the insulin effector protein kinase Akt in liver and adipose tissue of chow-fed UKO mice. We identified the Akt activator protein APPL1 as a Ube4A interactor. The K63-linked ubiquitination (K63-Ub) of Akt and APPL1, known to facilitate insulin-induced Akt activation, is impaired in UKO mice. Furthermore, Ube4A K63-ubiquitinates Akt in vitro.
Ube4A is a novel regulator of obesity, insulin resistance, adipose tissue dysfunction and NAFLD, and preventing its downregulation may ameliorate these diseases.
•The U-box containing E3 ubiquitin ligase Ube4A is a novel regulator of metabolism.•Deletion of Ube4A exacerbates high fat diet-induced obesity, hyperinsulinemia, and insulin resistance in both sexes of mice.•Ube4A deletion augments hepatic steatosis and enhances lipid uptake and lipogenesis in hepatocytes.•Ube4A facilitates insulin signaling by K63-ubiquitination of Akt and APPL1.•Maintaining Ube4A's activity may ameliorate obesity, T2DM and NAFLD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress ...glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high‐fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD‐fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.
Hepatic phospholipid (PL) saturation, mediated by depletion of a PL remodeling enzyme LPCAT3, protects mice from diet‐induced obesity through FGF21 and elevated energy expenditure. Ablation of Lpcat3 in the liver improves insulin sensitivity by facilitating insulin receptor endocytosis into early endosomes and glucose uptake in brown adipose tissue.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices.
To create ...opioid-prescribing consensus guidelines for common dermatologic procedures.
We used a 4-step modified Delphi method to conduct a systematic discussion among a panel of dermatologists in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naive patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents.
Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatologic scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23% of the procedural scenarios routinely require 1 to 10 opioid tablets, and only 1 routinely requires 1 to 15 opioid tablets.
These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients' comorbidities.
Procedure-specific opioid prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Idealized models or emulators of volcanic aerosol forcing have been widely used to reconstruct the spatiotemporal evolution of past volcanic forcing. However, existing models, including the most ...recently developed Easy Volcanic Aerosol (EVA; Toohey et al., doi: 10.5194/gmd‐2016‐83), (i) do not account for the height of injection of volcanic SO
2; (ii) prescribe a vertical structure for the forcing; and (iii) are often calibrated against a single eruption. We present a new idealized model, EVA_H, that addresses these limitations. Compared to EVA, EVA_H makes predictions of the global mean stratospheric aerosol optical depth that are (i) similar for the 1979–1998 period characterized by the large and high‐altitude tropical SO
2 injections of El Chichón (1982) and Mount Pinatubo (1991); (ii) significantly improved for the 1998–2015 period characterized by smaller eruptions with a large variety of injection latitudes and heights. Compared to EVA, the sensitivity of volcanic forcing to injection latitude and height in EVA_H is much more consistent with results from climate models that include interactive aerosol chemistry and microphysics, even though EVA_H remains less sensitive to eruption latitude than the latter models. We apply EVA_H to investigate potential biases and uncertainties in EVA‐based volcanic forcing data sets from phase 6 of the Coupled Model Intercomparison Project (CMIP6). EVA and EVA_H forcing reconstructions do not significantly differ for tropical high‐altitude volcanic injections. However, for high‐latitude or low‐altitude injections, our reconstructed forcing is significantly lower. This suggests that volcanic forcing in CMIP6 last millenium experiments may be overestimated for such eruptions.
Key Points
We present EVA_H, an observationally constrained volcanic forcing emulator accounting for the mass, latitude, and altitude of erupted SO
2
Accounting for the altitude of volcanic injections improves predictions of subsequent perturbations of stratospheric optical properties
EVA_H shows enhanced consistency with interactive stratospheric aerosol models, but still lacks sensitivity to eruption latitude
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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