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Abstract
We reported that microRNA-155 (miR-155) deficiency in ApoE-/- mice yields a novel metabolically healthy obese (MHO) model, which exhibits improved atherosclerosis but results in obesity, non-alcoholic fatty liver disease (NAFLD) without insulin resistance. Using experimental data mining approaches combined with experiments, we found that, among 109 miRNAs, miR-155, and miR-221 are significantly modulated in all four hyperlipidemia-related diseases (HRDs), namely atherosclerosis, NAFLD, obesity and type II diabetes (T2DM). MiR-155 is significantly upregulated in atherosclerosis and decreased in other HRDs. MiR-221 is increased in three HRDs but reduced in obesity. These findings led to our new classification of types I and II MHOs, which are regulated by miR-221 and miR-155, respectively. Western blots showed that the proinflammatory adipokine, resistin, is significantly increased in white adipose tissues (WAT) of the MHO mice, revealing our newly proposed, miR-155-suppressed “secondary wave inflammatory state (SWIS),” characteristic of MHO transition to classical obesity (CO). Taken together, we are first to show that MHO may have heterogeneity in comorbidities, and is therefore classified into type I, and type II MHOs; and that increased expression of resistin in miR-155-/- white adipose tissues may be a driver for SWIS in MHO transition to CO. Our findings provide novel insights into the pathogenesis of MHO, MHO transition to CO, hyperlipidemic pathways related to cancer, and new therapeutic targets.
Highlights
Hyperlipidemia, or high low-density lipoprotein cholesterol, is a condition affecting 78 million Americans (High, 2017) and is a well-documented risk factor for a number of co-morbidities
To corroborate our newly proposed Type II metabolically healthy obese (MHO) model, we show that the proinflammatory adipokine, resistin, is significantly increased in adipose tissue of our MHO mice following high-fat diet (HFD) feeding, revealing a miR-155-suppressed adipose-tissue generated inflammatory state, characteristic of MHO transition to classical obesity (Jung et al, 2017)
These results demonstrated that (1) increased plasma resistin is derived from increased expression of resistin in white adipose tissues; (2) resistin expression is suppressed by miR-155, resistin expression is increased in miR-155 dark cycle. MiR-155−/−/ApoE−/− (DKO) white adipose tissues; and (3) since resistin is a proinflammatory adipokine, high-fat diet induction of resistin upregulation in white adipose tissues makes resistin a potential significant mediator to drive “a second wave of inflammation” in the miR-155−/− MHO status, which is required to MHO transition to classical obesity
Summary
Hyperlipidemia, or high low-density lipoprotein cholesterol, is a condition affecting 78 million Americans (High, 2017) and is a well-documented risk factor for a number of co-morbidities. These include atherosclerosis, obesity, non-alcoholic fatty liver disease (NAFLD), and type II diabetes mellitus (T2DM) (Figure 1A). The molecular mechanisms involved in the Resistin: Possible Driver to CO manifestation and progression of hyperlipidemia, with respect to these co-morbidities, are not completely understood. MiRNAs have been firmly established as important regulators in a host of diseases, including cardiovascular disease, obesity, type II diabetes and NAFLD. Much remains to be understood regarding their overlap and function in hyperlipidemia-related pathologies
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