Premium
Mechanistic Study of Four Co‐Morbid Hyperlipidemia‐Related Pathologies Reveals NFκB and STAT3‐Mediated miR‐155 and miR‐221 Potentially Serve as Master Regulators, and Elucidates Metabolically Healthy Obese Model
Author(s) -
Johnson Candice,
Drummer Charles,
Virtue Anthony,
Gao Tracy,
Hernandez Miguel,
Singh Lexy,
Wang Hong,
Yang XiaoFeng
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.752.4
Subject(s) - hyperlipidemia , insulin resistance , fatty liver , hyperinsulinemia , microrna , biology , obesity , diabetes mellitus , bioinformatics , medicine , disease , endocrinology , gene , genetics
Hyperlipidemia afflicts more than 70 million Americans and is commonly linked with atherosclerosis, obesity, non‐alcoholic fatty liver disease (NAFLD) and type II diabetes. In recent years, microRNAs (miRNAs) have been firmly established as important regulators in these hyperlipidemia‐related pathologies. However, much remains to be understood regarding miRNAs' overlap and function within these hyperlipidemia‐related pathologies. Our recent JBC paper (PMID: 27856635) has shown that miRNA‐155 is significantly increased in atherosclerosis but reduced in high‐fat diet‐induced obesity. We published the findings that global miR‐155 deficiency in an atherosclerotic mouse background yielded a novel metabolically healthy obese mouse model, which exhibits improved atherosclerosis but resulted in obesity, NAFLD, and hyperinsulinemia without insulin resistance. Such a finding implied 1) a potent role of a single miRNA to differentially affect hyperlipidemia‐related diseases such that miRNAs achieve master gene candidacy status; and 2) a differential expression of downstream targets of miRNA in different cell types. In our current study, we sought to expand our understanding of the various miRNAs in these hyperlipidemia‐related conditions, specifically in regards to their expression direction, regulation and function. We hypothesized that miRNAs function as a potent master regulator that directs pathogenesis of hyperlipidemia‐related diseases where only a few miRNAs are shared between two or more hyperlipidemia‐related conditions (e.g., atherosclerosis, obesity, insulin resistance/type II diabetes and NAFLD). Using microarray and other experimentally verified‐based datamining approaches, we found that, among nearly 150 miRNAs, miR‐155 and miR‐221 are significantly modulated in all four hyperlipidemia‐related diseases. Our results also show a significant role for NFκB and STAT3 as upstream regulators for these and other miRNAs. Our datamining results identified mRNA targets that could contribute to the disease manifestations. Additionally, we identified groups of miRNAs that are unique to one hyperlipidemia‐related disease type as well as miRNAs that were modulated in comorbidities, which may be useful as future disease biomarkers in differentiation, diagnosis and prognosis. Taken together, we are first to show that NFκB‐ and STAT3‐mediated miR‐155 and miR‐221 potentially serve as master regulators for four co‐morbid hyperlipidemia‐related diseases. Support or Funding Information NIH‐NHLBI This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .