AUTHOR=Zeng Ting , Lv Jinrui , Liang Jiaxin , Xie Binling , Liu Ling , Tan Yuanyuan , Zhu Junwei , Jiang Jifan , Xie Huaping 

TITLE=Zebrafish cobll1a regulates lipid homeostasis via the RA signaling pathway

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1381362

DOI=10.3389/fcell.2024.1381362

ISSN=2296-634X

ABSTRACT=<sec><title>Background:</title><p>The <italic>COBLL1</italic> gene has been implicated in human central obesity, fasting insulin levels, type 2 diabetes, and blood lipid profiles. However, its molecular mechanisms remain largely unexplored.</p></sec><sec><title>Methods:</title><p>In this study, we established <italic>cobll1a</italic> mutant lines using the CRISPR/Cas9-mediated gene knockout technique. To further dissect the molecular underpinnings of <italic>cobll1a</italic> during early development, transcriptome sequencing and bioinformatics analysis was employed.</p></sec><sec><title>Results:</title><p>Our study showed that compared to the control, <italic>cobll1a</italic><sup>−/−</sup> zebrafish embryos exhibited impaired development of digestive organs, including the liver, intestine, and pancreas, at 4 days post-fertilization (dpf). Transcriptome sequencing and bioinformatics analysis results showed that in <italic>cobll1a</italic> knockout group, the expression level of genes in the Retinoic Acid (RA) signaling pathway was affected, and the expression level of lipid metabolism-related genes (<italic>fasn</italic>, <italic>scd</italic>, <italic>elovl2</italic>, <italic>elovl6</italic>, <italic>dgat1a</italic>, <italic>srebf1</italic> and <italic>srebf2</italic>) were significantly changed (<italic>p</italic> &lt; 0.01), leading to increased lipid synthesis and decreased lipid catabolism. The expression level of apolipoprotein genes (<italic>apoa1a</italic>, <italic>apoa1b</italic>, <italic>apoa2</italic>, <italic>apoa4a</italic>, <italic>apoa4b</italic>, and <italic>apoea</italic>) genes were downregulated.</p></sec><sec><title>Conclusion:</title><p>Our study suggest that the loss of <italic>cobll1a</italic> resulted in disrupted RA metabolism, reduced lipoprotein expression, and abnormal lipid transport, therefore contributing to lipid accumulation and deleterious effects on early liver development.</p></sec>