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    • Freinkel first reported in the late s that

    2022-01-27

    Freinkel first reported in the late 1960s that maternal hypertriglyceridemia benefits the fetus during starvation by increasing maternal consumption of triglyceride for ketone body synthesis giving the basis for “accelerated starvation” theory [4,5]. This maternal metabolic reprogramming during periods of inadequate food allows her to utilize her accumulated adipose depots for the synthesis of ketone bodies as alternative fuels which allows for the preservation of glucose and amino acids that are required for other essential processes [17]. Furthermore, the fetus benefits from this as ketones can cross the placental barrier freely unlike lipids and may be used by the fetus either as fuels or as anabolic substrates [18,19]. In the fasting state, plasma NEFAs levels were higher in aHepHKDC1-OE mice and are converted to acetyl-CoA by enhanced β-oxidation and ultimately ketone bodies, which act as an energy source for maternal and fetal tissues during fasting. Our data suggest that hepatic HKDC1 is influencing the ‘early starvation of pregnancy’ phenomenon. We need to next assess how hepatic HKDC1 may influence NEFA levels (possibly via adipose lipolysis) and hepatic ketogenesis pathways. Whether acetyl-CoA produced by β-oxidation forms ketone bodies or enters the citric Anti-Inflammatory Peptide 1 (TCA) cycle is determined by anaplerotic influx of TCA cycle intermediates [34]. The conversion of pyruvate to oxaloacetate (OAA) by pyruvate carboxylase (PC) is one of the most important sources of anaplerosis in the liver [34]. Pyruvate can also be converted to acetyl-CoA by oxidative decarboxylation mediated by the pyruvate dehydrogenase complex (PDC). PDC activity is inhibited via phosphorylation of the pyruvate dehydrogenase by increased expression of pyruvate dehydrogenase kinases (PDKs) during fasting or in IR states [[35], [36], [37]]. We found that PDK2 levels which is the major PDK responsible for regulation of PDC activity in the liver [[38], [39], [40]] to be significantly decreased in aHepHKDC1-OE mice. It has been reported that decreased PDC activity and enhanced pyruvate carboxylation due to hepatic IR contributes to increased gluconeogenesis in obese subjects with hepatic steatosis [41,42]. Because of competition for pyruvate, the balance between PDC and PC activity may play a critical role in metabolic dysfunction caused by IR. We found that liver PDK2 inhibition may reduce the anaplerotic flux of pyruvate into the TCA cycle thereby channeling more ketogenesis which serves as fuel in the fasting state (Fig. 6).
    Conclusion In sum, we observed that hepatic HKDC1 influences maternal glucose tolerance, where it also affects whole body insulin sensitivity, hepatic gluconeogenesis, and ketone production during pregnancy (Fig. 6). These changes, through hepatic expression of this novel hexokinase, collectively alter maternal nutrient balance. Next steps will be important to elucidate how HKDC1 mechanistically drives each of these metabolic changes, as we suggest one proposed mechanism for ketone production, and what the influence on fetal outcomes is. The following are the supplementary data related to this article.
    Author contributions
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    Acknowledgements BTL is supported by the National Institutes of Health under award number, R01DK104927-01A1 and Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, VA Merit (grant no. 1I01BX003382). MWK, MP, JCC, TCB and BTL report no conflict of interests.
    Introduction Natural silk fibroin (SF) from the silkworm Bombyx mori consists principally of primary sequences of alanine, glycine and serine combined with a small number of polar amino acids such as lysine, tyrosine and aspartic acid, that have amino, phenolic hydroxyl and carboxyl reactive sites, respectively, randomly distributed along the fibroin chains [1,2]. As a natural biomaterial, SF exhibits many advantages over artificial materials, such as morphological flexibility, low immunogenicity, good biocompatibility and outstanding mechanical performance [[3], [4], [5]]. It can thus be processed into diverse forms for controlled drug delivery, tissue engineering and many other clinical applications in the biomedical field [[6], [7], [8], [9], [10], [11], [12], [13]]. Recently, considerable effort has been expended developing SF and hydroxyapatite (HAp) biocomposites for bone tissue engineering, via the blending of SF with nano-HAp, mineralization of SF in simulated body fluid (SBF) among other methods [[14], [15], [16]]. It is widely accepted that increased negative charges in the fibroin matrix can promote biomimetic growth of HAp, due principally to the association between calcium ions and the carboxyl groups introduced into SF [17,18]. In a previous study, we prepared composites of SF-g-polyacrylic acid (PAA) via enzymatic graft copolymerization, with the result that more HAp crystals were observed during mineralization than were deposited on SF [19], accompanied by being a more suitable environment for osteoblast adhesion.