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  • Gupta, AbhishekOhio University (author)

Human CIDEC transgene improves lipid metabolism and protects against high-fat diet–induced glucose intolerance in mice

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • Elsevier BV,2022

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:4b440844-6cc2-4891-8a28-333a8bd1193a
  • https://lup.lub.lu.se/record/4b440844-6cc2-4891-8a28-333a8bd1193aURI
  • https://doi.org/10.1016/j.jbc.2022.102347DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Cell death–inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential ‘drug’ or a ‘druggable’ target to reverse obesity-induced lipotoxicity and glucose intolerance.

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  • Balakrishnan, BijinuOhio University (author)
  • Karki, ShakunBoston University (author)
  • Slayton, MarkOhio University (author)
  • Jash, SukantaBrown University (author)
  • Banerjee, SayaniBrown University (author)
  • Grahn, Tan Hooi MinLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Hematopoiesis and Gene Therapy,Lund University Research Groups(Swepub:lu)med-snt (author)
  • Jambunathan, SrikarthikaBoston University (author)
  • Disney, SarahOhio University (author)
  • Hussein, HebaallahaOhio University (author)
  • Kong, DongBoston Children's Hospital (author)
  • Lowell, Bradford B.Harvard Medical School,Beth Israel Deaconess Medical Center (author)
  • Natarajan, PurushothamanUniversity of West Virginia (author)
  • Reddy, Umesh K.University of West Virginia (author)
  • Gokce, NoyanBoston University (author)
  • Sharma, Vishva M.Ohio University (author)
  • Puri, VishwajeetOhio University (author)
  • Ohio UniversityBoston University (creator_code:org_t)

Related titles

  • In:Journal of Biological Chemistry: Elsevier BV298:90021-9258

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