Resumen
Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum–lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD–mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.
| Idioma original | English |
|---|---|
| Número de artículo | e2426338122 |
| Publicación | Proceedings of the National Academy of Sciences of the United States of America |
| Volumen | 122 |
| N.º | 17 |
| DOI | |
| Estado | Published - abr 29 2025 |
Nota bibliográfica
Publisher Copyright:Copyright © 2025 the Author(s).
Financiación
We would like to thank all members of the Tontonoz, Tarling-Vallim, and Villanueva Laboratories for valuable discussion and technical support. Confocal microscopy was performed at the UCLA Broad Stem Cell Microscopy Core. Seahorse respirometry was performed at the UCLA Bioenergetics Core. AAV packaging was performed at the University of Michigan Vector Core. Histology was performed at the UCLA Translational Pathology Core. RNA sequencing was performed at the UCLA Technology Center for Genomics & Bioinformatics. This work was supported by grant no. NIH R01 DK136150 to P.T. L.F.U. was supported by grant no. NIH F30 DK134050, a UCLA Molecular Biology Institute Philip Whitcome Fellowship, and NIH T32 G008042 to the UCLA-Caltech Medical Scientist Training Program. K.Q. was supported by grant no. NIH F30 DK 123986. ACKNOWLEDGMENTS. We would like to thank all members of the Tontonoz, Tarling-Vallim, and Villanueva Laboratories for valuable discussion and technical support. Confocal microscopy was performed at the UCLA Broad Stem Cell Microscopy Core. Seahorse respirometry was performed at the UCLA Bioenergetics Core. AAV packaging was performed at the University of Michigan Vector Core. Histology was performed at the UCLATranslational Pathology Core.RNAsequenc-ing was performed at the UCLATechnology Center for Genomics & Bioinformatics. This work was supported by grant no. NIH R01 DK136150 to P.T. L.F.U. was supported by grant no. NIH F30 DK134050, a UCLA Molecular Biology Institute Philip Whitcome Fellowship, and NIH T32 G008042 to the UCLA-Caltech Medical Scientist Training Program. K.Q. was supported by grant no. NIH F30 DK 123986.
| Financiadores | Número del financiador |
|---|---|
| Villanueva Laboratories | |
| National Institutes of Health (NIH) | F30 DK134050, R01 DK136150 |
| University of California, Los Angeles | T32 G008042 |
| UCLA-Caltech | NIH F30 DK 123986 |
ASJC Scopus subject areas
- General
Huella
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