FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

Lee, Seungmin; Lee, Seol Hee; Jung, Youngae; Lee, Younglang; Yoon, Jong Hyun; Choi, Jeong Yi; Hwang, Chae Young; Son, Young Hoon; Park, Sung Sup; Hwang, Geum‐Sook; Lee, Kwang-Pyo; Kwon, Ki‐Sun

doi:10.1038/s41467-020-19501-6

Cited by 87 publications

(62 citation statements)

References 48 publications

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“…Unlike glucose, lipid species are insoluble and generally bind to lipid chaperones for transportation and utilization. Among them, fatty acid binding protein 3 (FABP3) is a small protein that is abundantly expressed in heart tissues and participates in cell metabolism by binding free long-chain fatty acids (LCFAs) and transporting them for cell metabolism, thereby protecting against lipid toxicity (12,13). Additionally, FABP3 has been described in the context of cardiac hypertrophy, with a positive relationship being described between cellular and circulating levels of FABP3 and cardiac hypertrophy in patients and mice (14).…”

Section: Introductionmentioning

confidence: 99%

FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway

Zhuang

Liu

et al. 2021

Front. Cardiovasc. Med.

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Background: Cardiac hypertrophy was accompanied by various cardiovascular diseases (CVDs), and due to the high global incidence and mortality of CVDs, it has become increasingly critical to characterize the pathogenesis of cardiac hypertrophy. We aimed to determine the metabolic roles of fatty acid binding protein 3 (FABP3) on transverse aortic constriction (TAC)-induced cardiac hypertrophy.Methods and Results: Transverse aortic constriction or Ang II treatment markedly upregulated Fabp3 expression. Notably, Fabp3 ablation aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction. Multi-omics analysis revealed that Fabp3-deficient hearts exhibited disrupted metabolic signatures characterized by increased glycolysis, toxic lipid accumulation, and compromised fatty acid oxidation and ATP production under hypertrophic stimuli. Mechanistically, FABP3 mediated metabolic reprogramming by directly interacting with PPARα, which prevented its degradation and synergistically modulated its transcriptional activity on Mlycd and Gck. Finally, treatment with the PPARα agonist, fenofibrate, rescued the pro-hypertrophic effects of Fabp3 deficiency.Conclusions: Collectively, these findings reveal the indispensable roles of the FABP3–PPARα axis on metabolic homeostasis and the development of hypertrophy, which sheds new light on the treatment of hypertrophy.

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Section: Introductionmentioning

confidence: 99%

FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway

Zhuang

Liu

et al. 2021

Front. Cardiovasc. Med.

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“…FABP3 is highly expressed in skeletal muscle and works as a lipid chaperon, as consumption of high-fat diet increases its muscle expression 33 . FABP3 expression also increases in sarcopenic muscle and contributes to muscle atrophy and weakness by inducing endoplasmic reticulum stress 34 . We found higher levels of circulating FABP3 in the patient with COPD and CHF, which integrate with the contribution(s) of ER stress to skeletal muscle remodeling in COPD 35 and CHF 36 .…”

Section: Discussionmentioning

confidence: 99%

Prediction of sarcopenia using a battery of circulating biomarkers

Qaisar

Karim

Muhammad

et al. 2021

Sci Rep

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Loss of muscle mass and strength with aging, termed sarcopenia is accelerated in several comorbidities including chronic heart failure (CHF) and chronic obstructive pulmonary diseases (COPD). However, the effective circulating biomarkers to accurately diagnose and assess sarcopenia are not known. We recruited male healthy controls and patients with CHF and COPD (n = 81–87/group), aged 55–74 years. Sarcopenia was clinically identified based on hand-grip strength, appendicular skeletal muscle index and physical capacity as recommended by the European working group for sarcopenia. The serum levels of amino-terminal pro-peptide of type-III procollagen, c-terminal agrin fragment-22, osteonectin, irisin, fatty acid-binding protein-3 and macrophage migration inhibitory factor were significantly different between healthy controls and patients with CHF and COPD. Risk scores for individual biomarkers were calculated by logistic regressions and combined into a cumulative risk score. The median cutoff value of 3.86 was used to divide subjects into high- and low-risk groups for sarcopenia with the area under the curve of 0.793 (95% CI = 0.738–0.845, p < 0.001). A significantly higher incidence of clinical sarcopenia was found in high-risk group. Taken together, the battery of biomarkers can be an effective tool in the early diagnosis and assessment of sarcopenia.

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“…“Young” (3-month-old) and “Old” (24-month-old) mouse tibialis anterior muscle were isolated (approved by KRIBB-AEC-16143), homogenized, and lysed with a buffer containing 20 mM HEPES (pH 7.2), 150 mM NaCl, 0.5% Triton X-100, 0.1 mM Na 3 VO 4 , 1 mM NaF, 1 mM 4-(2-aminoethyl)-benzene sulfonyl fluoride hydrochloride, and 5 mg/mL aprotinin (Sigma-Aldrich). 34 The lysates were centrifuged at 15,000×g for 20 minutes at 4°C, and the supernatants were subjected to SDS-PAGE or acidic phenol extraction for RNA purification followed by immunoblot analysis.…”

Section: Methodsmentioning

confidence: 99%

Profiling of RNA-binding Proteins Interacting With Glucagon and Adipokinetic Hormone mRNAs

Yeom

Chun

et al. 2022

J Lipid Atheroscler

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Objective Glucagon in mammals and its homolog (adipokinetic hormone [AKH] in Drosophila melanogaster ) are peptide hormones which regulate lipid metabolism by breaking down triglycerides. Although regulatory mechanisms of glucagon and AKH expression have been widely studied, post-transcriptional gene expression of glucagon has not been investigated thoroughly. In this study, we aimed to profile proteins binding with Gcg messenger RNA (mRNA) in mouse and Akh mRNA in Drosophila. Methods Drosophila Schneider 2 (S2) and mouse 3T3-L1 cell lysates were utilized for affinity pull down of Akh and Gcg mRNA respectively using biotinylated anti-sense DNA oligoes against target mRNAs. Mass spectrometry and computational network analysis revealed mRNA-interacting proteins residing in functional proximity. Results We observed that 1) 91 proteins interact with Akh mRNA from S2 cell lysates, 2) 34 proteins interact with Gcg mRNA from 3T3-L1 cell lysates. 3) Akh mRNA interactome revealed clusters of ribosomes and known RNA-binding proteins (RBPs). 4) Gcg mRNA interactome revealed mRNA-binding proteins including Plekha7, zinc finger protein, carboxylase, lipase, histone proteins and a cytochrome, Cyp2c44. 5) Levels of Gcg mRNA and its interacting proteins are elevated in skeletal muscles isolated from old mice compared to ones from young mice. Conclusion Akh mRNA in S2 cells are under active translation in a complex of RBPs and ribosomes. Gcg mRNA in mouse precursor adipocyte is in a condition distinct from Akh mRNA due to biochemical interactions with a subset of RBPs and histones. We anticipate that our study contributes to investigating regulatory mechanisms of Gcg and Akh mRNA decay, translation, and localization.

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FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

Cited by 87 publications

References 48 publications

FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway

FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway

Prediction of sarcopenia using a battery of circulating biomarkers

Profiling of RNA-binding Proteins Interacting With Glucagon and Adipokinetic Hormone mRNAs

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