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    • Tenovin-1 In the intestine absorbed cholesterol can

    2021-07-17

    In the intestine, absorbed cholesterol can either be esterified by ACAT2 (Soat2) and packed into chylomicrons, transported back to the intestinal lumen by ABCG5/ABCG8, or it can be transported into HDL by ABCA1. ACAT2 is confined to enterocytes and hepatocytes and esterifies cholesterol for intracellular storage or secretion in chylomicrons or VLDL particles, respectively [38]. We have previously found TGIF1 to function as a repressor of SOAT2 and that Tgif1−/− mice have increased hepatic Soat2 mRNA expression levels [7]. However, overexpression of TGIF1 in the intestine did not significantly decrease intestinal or hepatic Soat2 mRNA expression levels. No significant effects were observed in intestinal or hepatic cholesterol levels nor did serum VLDL particles differ between Villin-Tgif1 and wild type mice. It is, therefore, possible that hepatocyte-specific overexpression of TGIF1 would more strongly affect Soat2. In summary, here we found TGIF1 to function as a repressor of NPC1L1 and overexpression of TGIF1 in the intestine of mice to lower markers of intestinal cholesterol Tenovin-1 and intestinal expression levels of Npc1l1, Abca1, Abcg5, and Abcg8. TGIF1 is thus a new player in intestinal cholesterol metabolism.
    Conflicts of interest
    Financial support This work was supported by grants from the Swedish Research Council, the Swedish Heart-Lung, and The Novo Nordisk Research Foundations, the Stockholm City Council, the Karolinska Institutet, and by a grant from the National Institutes of Health (R01 GM099853) to D.W.
    Author contributions
    Acknowledgements
    Peptide arrays have received much attention as tools for identifying linear peptides with specific activities, such as antibody binding, enzyme inhibition, cell surface binding, and so on. Our group has already identified several high-binding peptides, with high affinity to various targets including for example angiotensin , amylase , IgG , , IL-2 , bile acid , apoptosis-inducing peptides , , and cell adhesive peptides , . Cholesterol absorption in the upper intestine is facilitated by bile acid micelles, which can capture cholesterol. Inhibition of bile acid micelle formation can suppress intestinal cholesterol absorption . Thus, bile acid binding peptides could be expected to inhibit cholesterol absorption. It was reported that VAWWMY (Val-Ala-Trp-Trp-Met-Tyr), the hydrophobic 6-mer peptide in the glycinin A1a and B1b subunits of soybean protein, has inhibitory effects on cholesterol absorption and lowers serum cholesterol , , . Therefore, our group screened 6-mer peptides, replacing each position of VAWWMY with another amino acid (unpublished data). Our group also performed computationally assisted screening from a random 6-mer library (2212 sequences), and found a positional rule for identifying high-binding peptides. According to that rule, about 33% of the peptides from the spot-synthesized peptide array evaluation were indicated to have high-binding tendencies .
    Introduction Cardiovascular diseases (CVDs) constitute the leading cause of mortality and morbidity worldwide and are caused primarily by complications of atherosclerosis [1]. Atherosclerosis is a slow and progressive disease, which is characterized by abnormal accumulation of lipids in the large and medium-sized arteries [2], [3]. Epidemiological studies have revealed numerous risk factors, including dietary pattern, physical inactivity, dyslipidemia, diabetes mellitus, smoking, obesity and psychological stress associated with the initiation and development of atherosclerosis and its clinical manifestations [4]. A growing number of studies have shown that higher dietary fiber intake was associated with a reduced risk of atherosclerotic CVD incidence and maintenance of whole-body cholesterol homeostasis; however, the related molecular mechanism is not fully elucidated. Dietary fiber comprises the indigestible complex carbohydrates mainly derived from plants, which can be divided into two categories: insoluble and soluble fibers. Insoluble fibers are only marginally fermented with the properties of bulking action, whereas soluble fibers, which can be dissolved in water, are easily fermented by a wide variety of anaerobic intestinal microbiota in the human colon, leading to an increase in physiologically active byproducts such as short-chain fatty acids (SCFAs) [5], [6]. The most commonly occurring SCFAs are acetate, propionate and butyrate, which are present in an approximate molar ratio of 60:20:20 in the colon and stool [7]. Previous study has shown that the total concentration of SCFAs was ranging from 70–140 mmol/L in the proximal colon to 20–70 mmol/L in the distal colon depending on the different dietary patterns [8].