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  • Notably the basal levels insulin of


    Notably, the basal levels (−insulin) of glucose uptake by isolated soleus muscle in lcat mice are significantly lower from the levels measured in the control C57BL/6 group, while stimulated levels (+insulin) reach those of the basal levels of the control group. These findings may indicate a shift from glucose metabolism to fatty E-64-c oxidation and lower demand for glucose in lcat mice. Yet, their soleus muscles remain highly sensitive to insulin stimulation at either week or 24 (Fig. 6A, B, +insulin) indicating no induction of insulin resistance in the muscle of these animals following feeding the high fat diet.
    Conclusions Taken together, our data suggest that universal deletion of apoa1 and lcat in mice fed western-type diet correlates with discreet effects on WAT metabolic activation and plasma glucose homeostasis. Apoa1-deficiency results in reduced WAT mitochondrial non-shivering thermogenesis. However, Lcat-deficiency causes a concerted reduction in both WAT oxidative phosphorylation and non-shivering thermogenesis, rendering lcat mice the most sensitive in weight gain out of the three strains tested, followed by apoa1 mice. Nevertheless, only apoa1 mice show disturbed plasma glucose homeostasis due to non-responsive pancreatic β-islets to glucose and insulin resistant skeletal muscles. Our analyses show that both apoa1 and lcat mice fed high-fat diet have no measurable Apoa1 levels in their plasma, suggesting that other HDL components may be responsible for the observed phenotypic differences of these groups. The precise role of Apoc2-HDL that is mainly present in apoa1 mice and Apoa2-HDL that is mainly present in the circulation of lcat mice on WAT metabolic activation, pancreatic β-islet function and peripheral insulin resistance remain to be investigated. Our data further indicate that changes in plasma apolipoprotein levels induced by hypolipidemic medications may impact WAT energy metabolism and glucose tolerance. It should be investigated if the weight gain and glucose intolerance associated with long term use of hypolipidemic medications, such as statins [50], is the result of altered plasma apolipoprotein levels triggered by these medications.
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    Author contributions
    Conflict of interest
    Funding The authors of this article have collaborated in the framework of COST Action CM1201. Ms. E. Xepapadaki received funding for a short-term scientific mission (STSM) by the above COST action to visit the Hebrew University of Jerusalem, where she was trained on islet physiology in S. Sasson's laboratory (COST STSM Reference Number: COST-STSM-CM1201-16404). Ms. E. Xepapadaki and Dr. E. Karavia are currently supported by a graduate studentship (2017–2019) and a postdoctoral fellowship (2017–2019) respectively, funded by the Hellenic Scholarship Foundation (IKY). The work was supported by the project “INSPIRED - U OF PATRAS.” (MIS 5002550) of the Hellenic General Secreteriat for Research and Technology (GSRT), which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).
    Introduction N-myc downstream regulated gene 1 (NDRG1) is a potent metastasis suppressor, which inhibits multiple oncogenic signaling pathways in various cancers [1,2]. Indeed, its anti-oncogenic functions have been demonstrated in vitro [[3], [4], [5]] and in vivo [6,7], making this protein an important therapeutic target for development of novel anti-cancer therapies. While the molecular functions of NDRG1 have been elucidated in various cancers [2], including its role as a broad inhibitor of oncogenic signaling [3,4,[8], [9], [10]], the exact mechanism(s) involved in its cellular processing and degradation remain elusive. The NDRG1 gene, which is located on chromosome 8q24.3 [11], encodes a 3.0-kb mRNA that translates to a protein comprised of 394 amino acids [12,13]. NDRG1 is a member of the NDRG family, which consists of four family members, NDRG1–4 [14]. Unlike other NDRG members, NDRG1 E-64-c has a three tandem (GTRSRSHTSE) repeat sequences near its C-terminus end [14]. Assessment of NDRG1 protein expression by immunoblotting revealed the existence of multiple isoforms of the protein in six different tumor cell-types, with two major bands at ~41- and ~46-kDa and a faint third band that was differentially expressed between the cell-types at ~47-kDa [15].