Fitm2 is required for ER homeostasis and normal function of murine liver Journal Article
| Authors: | Bond, L. M.; Ibrahim, A.; Lai, Z. W.; Walzem, R. L.; Bronson, R. T.; Ilkayeva, O. R.; Walther, T. C.; Farese, R. V. Jr |
| Article Title: | Fitm2 is required for ER homeostasis and normal function of murine liver |
| Abstract: | The endoplasmic reticulum (ER)–resident protein fat storage–inducing transmembrane protein 2 (FIT2) catalyzes acyl-CoA cleavage in vitro and is required for ER homeostasis and normal lipid storage in cells. The gene encoding FIT2 is essential for the viability of mice and worms. Whether FIT2 acts as an acyl-CoA diphosphatase in vivo and how this activity affects the liver, where the protein was discovered, are unknown. Here, we report that hepatocyte-specific Fitm2 knockout (FIT2-LKO) mice fed a chow diet exhibited elevated acyl-CoA levels, ER stress, and signs of liver injury. These mice also had more triglycerides in their livers than control littermates due, in part, to impaired secretion of triglyceride-rich lipoproteins and reduced capacity for fatty acid oxidation. We found that challenging FIT2-LKO mice with a high-fat diet worsened hepatic ER stress and liver injury but unexpectedly reversed the steatosis phenotype, similar to what is observed in FIT2-deficient cells loaded with fatty acids. Our findings support the model that FIT2 acts as an acyl-CoA diphosphatase in vivo and is crucial for normal hepatocyte function and ER homeostasis in the murine liver. © 2023 The Authors |
| Keywords: | proteins; endoplasmic reticulum; liver; in-vivo; fatty acids; mammals; lipid metabolism; diseases; gene encoding; endoplasmic reticulum stress; transmembrane proteins; homoeostasis; acyl-coa; lipid metabolisms; fitm2; liver injuries; trans-membrane proteins |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 299 |
| Issue: | 3 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2023-03-01 |
| Start Page: | 103022 |
| Language: | English |
| DOI: | 10.1016/j.jbc.2023.103022 |
| PUBMED: | 36805337 |
| PROVIDER: | scopus |
| PMCID: | PMC10027564 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding authors are Tobias Walther and Robert Farese -- Source: Scopus |
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