Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Ferrara, Patrick J.; Rong, Xianglu; Maschek, J. Alan; Verkerke, Anthony R.P.; Siripoksup, Piyarat; Song, Houyan; Green, Thomas D.; Krishnan, Karthickeyan Chella; Johnson, Jordan M.; Turk, John; Houmard, Joseph A.; Lusis, Aldons J.; Drummond, Micah J.; McClung, Joseph M.; Cox, James E.; Shaikh, Saame Raza; Tontonoz, Peter; Holland, William L.; Funai, Katsuhiko

doi:10.1172/jci135963

Cited by 49 publications

(84 citation statements)

References 78 publications

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“…LXR activation promotes the entry of unsaturated fatty acids into PLs through LPCAT3, thereby reducing liver ERS and inflammation ( Rong et al, 2013 ). Patrick et al ( Ferrara et al, 2021 ) found that mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance.…”

Section: Discussionmentioning

confidence: 99%

Kaempferol Alleviates Steatosis and Inflammation During Early Non-Alcoholic Steatohepatitis Associated With Liver X Receptor α-Lysophosphatidylcholine Acyltransferase 3 Signaling Pathway

et al. 2021

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Background: Kaempferol (KP) has a variety of biological effects such as anti-inflammatory, anti-oxidant, anti-aging and cardiovascular protection. Whether KP has a therapeutic effect on non-alcoholic steatohepatitis (NASH), and the detailed mechanism is currently unclear. This study aims to explore the mechanism of KP in the treatment of NASH through in vivo and in vitro experiments.Methods: 1) In vivo experiment: In the C57BL/6 NASH mice model induced by high fat diet (HFD), KP was administered by gavage at a dose of 20 mg/kg/day. 2) In vitro experiment: Palmitic acid/Oleic acid (PA/OA, 0.375/0.75 mM) was used to intervene HepG2 and AML12 cells to establish a steatosis cell model. Three concentrations of KP, low (20 μmol/L), medium (40 μmol/L) and high (60 μmol/L) were used in vitro. The mRNA and protein expression of related molecules involved in LXRα-LPCAT3-ERS pathway were detected using RT-qPCR and Western blot.Results: In the NASH mouse model, KP can significantly reduce the expression of LXRα, LPCAT3 and ERS-related factors PERK, eIF2α, ATF6, ATF4, XBP1, CHOP, IRE1α and GRP78. In the PA/OA-induced cell model, KP could decrease the content of triglyceride and lipid droplets, and also decrease the expression of LXR α, LPCAT3 and ERS related factors PERK, eIF2α, ATF6, ATF4, XBP1, CHOP, IRE1α and GRP78.Conclusion: KP may decrease the expression level of LXRα and LPCAT3, thus improve ERS and reduce hepatic steatosis and inflammation.

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Section: Discussionmentioning

confidence: 99%

Kaempferol Alleviates Steatosis and Inflammation During Early Non-Alcoholic Steatohepatitis Associated With Liver X Receptor α-Lysophosphatidylcholine Acyltransferase 3 Signaling Pathway

et al. 2021

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“…Force production in extensor digitorum longus (EDL) muscle was measured as previously described. 14,18,29 Briefly, EDL muscles were sutured at each tendon and placed in a tissue bath (Aurora Scientific, Model 801C). The optimal length (L o ) of each muscle was determined by pulse stimulation.…”

Section: Skeletal Muscle Force Productionmentioning

confidence: 99%

“…14 Mice with tamoxifen-inducible skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) were generated. 14 This strategy successfully yielded mice with increased LPCAT3 transcript and protein in skeletal muscle (Figures 2A and S1A). Body and fat masses were not different between the groups (Figure 2B,C).…”

Section: Skeletal Muscle-specific Overexpression Of Lpcat3 Lowers Lyso-pc and Lyso-pe Without Robustly Affecting Other Classes Of Lipidsmentioning

confidence: 99%

Low lysophosphatidylcholine induces skeletal muscle myopathy that is aggravated by high‐fat diet feeding

et al. 2021

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Obesity alters skeletal muscle lipidome and promotes myopathy, but it is unknown whether aberrant muscle lipidome contributes to the reduction in skeletal muscle contractile force-generating capacity. Comprehensive lipidomic analyses of mouse skeletal muscle revealed a very strong positive correlation between the abundance of lysophosphatidylcholine (lyso-PC), a class of lipids that is known to be downregulated with obesity, with maximal tetanic force production. The level of lyso-PC is regulated primarily by lyso-PC acyltransferase 3 (LPCAT3), which acylates lyso-PC to form phosphatidylcholine. Tamoxifen-inducible skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) was sufficient to reduce muscle lyso-PC content in both standard chow diet-and high-fat diet (HFD)-fed conditions. Strikingly, the assessment of skeletal muscle force-generating capacity ex vivo revealed that muscles from LPCAT3-MKI mice were weaker regardless of diet. Defects in force production were more apparent in HFD-fed condition, where tetanic force production was 40% lower in muscles from LPCAT3-MKI compared to that of control

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“…Interestingly, this LPC/PC ratio has just been proposed as a factor capable of modulating the physical properties of cell membranes and the activity of membrane receptors. Indeed, a lipidomic analysis recently performed on primary myocytes from individuals that are insulin-sensitive and lean or insulin-resistant with obesity (OB) also revealed a global phospholipidome downmodulation in OB myotubes [25]. Authors underlined the specific decrease in the LPC/PC ratio in these OB myotubes that resulted from a greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle).…”

Section: Discussionmentioning

confidence: 99%

“…Because previous studies suggest that altering the LPC/PC ratio of cell membranes is sufficient to disrupt the physical properties of membranes [25], we also focused on the Lyso-PL/PL ratios. Interestingly, the LPC/PC ratio is significantly decreased in OBDysG individuals when compared to OBNG patients (Figure 7).…”

Section: A Few Individual Phospholipidic Species Allow To Distinguish Obese Patients With Dysglycemia From Normoglycemic Obese Individualmentioning

confidence: 99%

New Insights on the PBMCs Phospholipidome in Obesity Demonstrate Modulations Associated with Insulin Resistance and Glycemic Status

et al. 2021

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(1) Background: Obesity and type 2 diabetes have been suspected to impact both intrinsic metabolism and function of circulating immune cells. (2) Methods: To further investigate this immunometabolic modulation, we profiled the phospholipidome of the peripheral blood mononuclear cells (PBMCs) in lean, normoglycemic obese (OBNG) and obese with dysglycemia (OBDysG) individuals. (3) Results: The global PBMCs phospholipidome is significantly downmodulated in OBDysG unlike OBNG patients when compared to lean ones. Multiple linear regression analyses show a strong negative relationship between the global PBMCs phospholipidome and parameters assessing insulin resistance. Even though all classes of phospholipid are affected, the relative abundance of each class is maintained with the exception of Lyso-PC/PC and Lyso-PE/PE ratios that are downmodulated in PBMCs of OBDysG compared to OBNG individuals. Interestingly, the percentage of saturated PC is positively associated with glycated hemoglobin (HbA1c). Moreover, a few lipid species are significantly downmodulated in PBMCs of OBDysG compared to OBNG individuals, making possible to distinguish the two phenotypes. (4) Conclusions: This lipidomic study highlights for the first-time modulations of the PBMCs phospholipidome in obese patients with prediabetes and type 2 diabetes. Such phospholipidome remodeling could disrupt the cell membranes and the lipid mediator’s levels, driving an immune cell dysfunction.

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Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

Cited by 49 publications

References 78 publications

Kaempferol Alleviates Steatosis and Inflammation During Early Non-Alcoholic Steatohepatitis Associated With Liver X Receptor α-Lysophosphatidylcholine Acyltransferase 3 Signaling Pathway

Kaempferol Alleviates Steatosis and Inflammation During Early Non-Alcoholic Steatohepatitis Associated With Liver X Receptor α-Lysophosphatidylcholine Acyltransferase 3 Signaling Pathway

Low lysophosphatidylcholine induces skeletal muscle myopathy that is aggravated by high‐fat diet feeding

New Insights on the PBMCs Phospholipidome in Obesity Demonstrate Modulations Associated with Insulin Resistance and Glycemic Status

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