Human CEACAM1-LF regulates lipid storage in HepG2 cells via fatty acid transporter CD36

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in the liver and secreted as biliary glycoprotein 1 (BGP1) via bile canaliculi (BCs). CEACAM1-LF is a 72 amino acid cytoplasmic domain mRNA splice isoform with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Ceacam1−/− or Ser503Ala transgenic mice have been shown to develop insulin resistance and nonalcoholic fatty liver disease; however, the role of the human equivalent residue, Ser508, in lipid dysregulation is unknown. Human HepG2 hepatocytes that express CEACAM1 and form BC in vitro were compared with CEACAM1−/− cells and CEACAM1−/− cells expressing Ser508Ala null or Ser508Asp phosphorylation mimic mutations or to phosphorylation null mutations in the tyrosine ITIMs known to be phosphorylated by the tyrosine kinase Src. CEACAM1−/− cells and the Ser508Asp and Tyr520Phe mutants strongly retained lipids, while Ser508Ala and Tyr493Phe mutants had low lipid levels compared with wild-type cells, indicating that the ITIM mutants phenocopied the Ser508 mutants. We found that the fatty acid transporter CD36 was upregulated in the S508A mutant, coexpressed in BCs with CEACAM1, co-IPed with CEACAM1 and Src, and when downregulated via RNAi, an increase in lipid droplet content was observed. Nuclear translocation of CD36 associated kinase LKB1 was increased sevenfold in the S508A mutant versus CEACAM1−/− cells and correlated with increased activation of CD36-associated kinase AMPK in CEACAM1−/− cells. Thus, while CEACAM1−/− HepG2 cells upregulate lipid storage similar to Ceacam1−/− in murine liver, the null mutation Ser508Ala led to decreased lipid storage, emphasizing evolutionary changes between the CEACAM1 genes in mouse and humans. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in the liver and secreted as biliary glycoprotein 1 (BGP1) via bile canaliculi (BCs). CEACAM1-LF is a 72 amino acid cytoplasmic domain mRNA splice isoform with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Ceacam1−/− or Ser503Ala transgenic mice have been shown to develop insulin resistance and nonalcoholic fatty liver disease; however, the role of the human equivalent residue, Ser508, in lipid dysregulation is unknown. Human HepG2 hepatocytes that express CEACAM1 and form BC in vitro were compared with CEACAM1−/− cells and CEACAM1−/− cells expressing Ser508Ala null or Ser508Asp phosphorylation mimic mutations or to phosphorylation null mutations in the tyrosine ITIMs known to be phosphorylated by the tyrosine kinase Src. CEACAM1−/− cells and the Ser508Asp and Tyr520Phe mutants strongly retained lipids, while Ser508Ala and Tyr493Phe mutants had low lipid levels compared with wild-type cells, indicating that the ITIM mutants phenocopied the Ser508 mutants. We found that the fatty acid transporter CD36 was upregulated in the S508A mutant, coexpressed in BCs with CEACAM1, co-IPed with CEACAM1 and Src, and when downregulated via RNAi, an increase in lipid droplet content was observed. Nuclear translocation of CD36 associated kinase LKB1 was increased sevenfold in the S508A mutant versus CEACAM1−/− cells and correlated with increased activation of CD36-associated kinase AMPK in CEACAM1−/− cells. Thus, while CEACAM1−/− HepG2 cells upregulate lipid storage similar to Ceacam1−/− in murine liver, the null mutation Ser508Ala led to decreased lipid storage, emphasizing evolutionary changes between the CEACAM1 genes in mouse and humans. The liver plays a central role in lipid homeostasis, including the production of bile that contains both cholesterol and phospholipids. Biliary glycoprotein 1 (BGP1) is the major protein of bile (1Svenberg T. Hammarstrom S. Zeromski J. Immunofluorescence studies on the occurrence and localization of the CEA-related biliary glycoprotein I (BGP I) in normal human gastrointestinal tissues.Clin. Exp. Immunol. 1979; 36: 436-441PubMed Google Scholar). BGP1, now known as CEACAM1 (2Beauchemin N. Draber P. Dveksler G. Gold P. Gray-Owen S. Grunert F. Hammarstrom S. Holmes K.V. Karlsson A. Kuroki M. Lin S.H. Lucka L. Najjar S.M. Neumaier M. Obrink B. et al.Redefined nomenclature of the Google is expressed on the of hepatocytes and bile canaliculi and as a of insulin is insulin in Najjar S.M. CEACAM1 insulin in Google Scholar). CEACAM1 to cholesterol in bile M. L. L. Draber P. F. Kuroki M. 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Google Scholar). of ITIMs that phosphorylated by and tyrosine versus a cell Google CEACAM1-LF is phosphorylated by J. Neumaier M. of with biliary glycoprotein an adhesion molecule of the downregulated in Google and M. L. P. T. A. N. The of biliary glycoprotein tyrosine phosphorylation and with and in Google N. T. J. B. A. of biliary glycoprotein with protein tyrosine in Google Scholar). The of to the insulin in the liver been shown and insulin resistance S. A. and the and of insulin Google Scholar). Ceacam1−/− mice and with and develop nonalcoholic fatty liver on normal N. M. S. N. of the antigen-related cell adhesion molecule 1 to in a murine of Google Scholar). The mutation Ser503Ala in transgenic mice had a similar to Ceacam1−/− a G. L. Najjar S.M. of nonalcoholic in antigen-related cell adhesion molecule 1 mutant Google S. M. Najjar S.M. with null mutation of I develop nonalcoholic Google Scholar). The of the Ser503Ala null mutation in mice was to of insulin Najjar S.M. 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