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  • In summary our present work establishes the ability of the

    2021-07-27

    In summary, our present work establishes the ability of the mammalian intestine to function as an environmental sensor able to retain an active metabolic memory for early postnatal nutritional conditions. Epigenetic silencing of the expression of the main cholesterol Vincristine synthesis transporter Npc1l1 conceivably conveys the programming effect in our model. The precise molecular mechanisms of how decreased sterol absorption for a defined period of time translates into an altered epigenetic make-up, however, remains to be elucidated by future studies. We expect that our experimental model will be helpful in such an approach. From a clinical perspective, genetic variation at the Npc1l1 locus is associated with significant cardiovascular disease-related health benefits. Thus, our data might not be relevant only to understand programming events elicited by differential infant nutrition, but also to develop approaches to impact cardiovascular health positively in adulthood on a population level by interventions as early as during the breast-feeding period. Acknowledgments
    Introduction Transforming growth factor β induced factor homeobox 1 (TGIF1) was named TG-interacting factor 1 when discovered. TGIF1 is commonly known as a transcriptional repressor which limits the transcriptional output of transforming growth factor β-signaling (TGFβ) [[1], [2], [3]]. TGIF1 can be recruited to DNA via interaction with TGFβ-activated Smad transcription factors, or can repress transcription independent of TGFβ. TGIF1 exerts repression of target genes by binding to its cognate binding site or to binding sites for retinoid X receptor α (RXRα) [4,5]. RXRα is a heterodimeric partner of several nuclear receptors (e.g. peroxisome proliferator-activated receptor α and liver X receptor α; LXRα). Hence, TGIF1 may modulate other nuclear receptor responses, and we have previously shown that TGIF1 can repress some LXRα-regulated genes [6]. Although we have previously shown strong evidence that TGIF1 plays a role in regulating lipid metabolism, its roles is not fully characterized. We previously showed that knock-down of TGIF1 in human hepatoma HepG2 cells increased the expression of the two LXRα target genes, the ATP-binding cassette transporter A1 (ABCA1) and sterol regulatory element binding protein 1c (SREBF1) genes [6]. We also found mice lacking Tgif1 to have higher hepatic apolipoprotein (apo) c2 and a4 (Apoc2 and Apoa4) expression levels, two other Lxrα target genes, compared to wild type mice [6]. In a second study, we identified TGIF1 to function as a transcriptional repressor of the gene Sterol O-acyltransferase 2 (Soat2) that encodes for the cholesterol esterifying enzyme acyl-Coenzyme A:cholesterol acyltransferase 2 (ACAT2) [7]. TGIF1 was also found to be able to oppose the induction of the promoter activity of SOAT2 by hepatocyte nuclear factor (HNF) 1α and 4α in hepatic and intestinal cells. Moreover, Tgif1−/− mice have more hepatic lipid accumulation and higher serum cholesterol levels [7]. Niemann-Pick C1 like 1 (NPC1L1) localizes to the brush border membrane of enterocytes and mediates intestinal cholesterol absorption [8]. Sterols transported by NPC1L1 are selectively esterified by ACAT2 to generate cholesteryl esters, which can be packed into chylomicrons and secreted to lymph. Mice lacking Npc1l1 have more than 70% lower intestinal cholesterol absorption but serum cholesterol levels do not differ compared to controls due to a compensatory higher cholesterol synthesis [[8], [9], [10]]. In humans, heterozygous carriers of NPC1L1 inactivating mutations were recently reported to have ∼0.3 mmol/L lower low density lipoprotein (LDL) cholesterol concentrations, which was associated with a more than 50% relative reduced risk of coronary heart disease compared to noncarriers [11]. NPC1L1 is a target for the drug ezetimibe, which is used to treat patients with elevated serum cholesterol levels [8,9]. Treatment with ezetimibe as monotherapy lowers serum LDL cholesterol levels by ∼17% [12,13], and ezetimibe in combination therapy with cholesterol synthesis inhibitors (i.e., statins) leads to additional reductions of LDL cholesterol [14,15] and decreased mortality in patients with acute coronary syndrome [16].