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1.
Prog Lipid Res ; 93: 101265, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37979798

ABSTRACT

Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders.


Subject(s)
Cardiovascular Diseases , Nervous System Diseases , Humans , Oxylipins/metabolism , Apolipoprotein E4/metabolism , Lipoproteins/metabolism , Cardiovascular Diseases/metabolism
2.
J Lipid Res ; 64(5): 100353, 2023 05.
Article in English | MEDLINE | ID: mdl-36907552

ABSTRACT

Oxylipins are produced enzymatically from polyunsaturated fatty acids, are abundant in triglyceride-rich lipoproteins (TGRLs), and mediate inflammatory processes. Inflammation elevates TGRL concentrations, but it is unknown if the fatty acid and oxylipin compositions change. In this study, we investigated the effect of prescription ω-3 acid ethyl esters (P-OM3; 3.4 g/d EPA + DHA) on the lipid response to an endotoxin challenge (lipopolysaccharide; 0.6 ng/kg body weight). Healthy young men (N = 17) were assigned 8-12 weeks of P-OM3 and olive oil control in a randomized order crossover study. Following each treatment period, subjects received endotoxin challenge, and the time-dependent TGRL composition was observed. Postchallenge, arachidonic acid was 16% [95% CI: 4%, 28%] lower than baseline at 8 h with control. P-OM3 increased TGRL ω-3 fatty acids (EPA 24% [15%, 34%]; DHA 14% [5%, 24%]). The timing of ω-6 oxylipin responses differed by class; arachidonic acid-derived alcohols peaked at 2 h, while linoleic acid-derived alcohols peaked at 4 h (pint = 0.006). P-OM3 increased EPA alcohols by 161% [68%, 305%] and DHA epoxides by 178% [47%, 427%] at 4 h compared to control. In conclusion, this study shows that TGRL fatty acid and oxylipin composition changes following endotoxin challenge. P-OM3 alters the TGRL response to endotoxin challenge by increasing availability of ω-3 oxylipins for resolution of the inflammatory response.


Subject(s)
Fatty Acids, Omega-3 , Oxylipins , Male , Humans , Esters/pharmacology , Endotoxins , Cross-Over Studies , Fatty Acids, Omega-3/pharmacology , Eicosapentaenoic Acid/pharmacology , Lipoproteins , Triglycerides , Fatty Acids , Arachidonic Acid , Alcohols , Docosahexaenoic Acids/pharmacology
3.
Physiology (Bethesda) ; 37(6): 311-322, 2022 11 01.
Article in English | MEDLINE | ID: mdl-35944007

ABSTRACT

A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.


Subject(s)
Cardiovascular Diseases , Fatty Acids, Omega-3 , Fatty Acids, Nonesterified , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-3/therapeutic use , Humans , Inflammation , Signal Transduction
4.
Cardiovasc Res ; 118(4): 1061-1073, 2022 03 16.
Article in English | MEDLINE | ID: mdl-33752243

ABSTRACT

AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. CONCLUSION: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.


Subject(s)
Fatty Acids, Nonesterified , Heart Failure , Animals , Eicosapentaenoic Acid/pharmacology , Fatty Acids , Heart Failure/genetics , Heart Failure/prevention & control , Humans , Mice , Mice, Inbred C57BL , Oxylipins , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism
5.
J Biol Chem ; 293(23): 8734-8749, 2018 06 08.
Article in English | MEDLINE | ID: mdl-29610273

ABSTRACT

G protein-coupled receptors that signal through Gαq (Gq receptors), such as α1-adrenergic receptors (α1-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cß1 (PLCß1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. Despite these common proximal signaling mechanisms, Gq receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, Gq receptors are thought to induce myocyte hypertrophy through a mechanism termed excitation-transcription coupling, which provides a mechanistic basis for compartmentalization of calcium required for contraction versus IP3-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of Gq-receptor signaling as a mechanistic basis for unique Gq receptor-induced hypertrophic phenotypes in cardiac myocytes. We show that α1-ARs co-localize with PLCß1 and PIP2 at the nuclear membrane. Further, nuclear α1-ARs induced intranuclear PLCß1 activity, leading to histone deacetylase 5 (HDAC5) export and a robust transcriptional response (i.e. significant up- or down-regulation of 806 genes). Conversely, we found that angiotensin receptors localize to the sarcolemma and induce sarcolemmal PLCß1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of α1-AR-induced transcription. In summary, these results link Gq-receptor compartmentalization in cardiac myocytes to unique hypertrophic transcription. They suggest a new model of excitation-transcription coupling in adult cardiac myocytes that accounts for differential Gq-receptor localization and better explains distinct physiological functions of Gq receptors.


Subject(s)
Cardiomegaly/pathology , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Myocytes, Cardiac/pathology , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phospholipase C beta/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Signal Transduction , Active Transport, Cell Nucleus , Animals , Cardiomegaly/genetics , Cardiomegaly/metabolism , Cell Nucleus/metabolism , Cell Nucleus/pathology , Female , GTP-Binding Protein alpha Subunits, Gq-G11/analysis , Histone Deacetylases/analysis , Histone Deacetylases/metabolism , Male , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Nuclear Envelope/metabolism , Nuclear Envelope/pathology , Phenotype , Phosphatidylinositol 4,5-Diphosphate/analysis , Phospholipase C beta/analysis , Receptors, Adrenergic, alpha-1/analysis , Sarcolemma/metabolism , Sarcolemma/pathology , Transcriptional Activation
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