Abstract
In cell models, changes in the ‘accessible’ pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis.
| Original language | English |
|---|---|
| Pages (from-to) | 165-181 |
| Number of pages | 17 |
| Journal | Nature Metabolism |
| Volume | 5 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2023 |
Bibliographical note
Publisher Copyright:© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Funding
We thank all members of the Tontonoz, Tarling-Vallim, Edwards, Villanueva, Young and Bensinger laboratories at UCLA for useful advice and discussions and for sharing reagents and resources. We thank K. Williams, G. Su and staff at UCLA Lipidomics core for the lipidomics analysis. Confocal microscopy was performed at the California NanoSystems Institute of Advanced Light Microscopy/Spectroscopy Facility. We thank the Vector Core of the University of Michigan for AAV packaging. We thank J. Smothers and A. Radhakrishnan for the helpful suggestions about the ALOD4 protein purification. This work was supported by NIH grant R01 DK126779 and Fondation Leducq Transatlantic Network of Excellence (19CVD04). X.X. was supported by AHA Postdoctoral Fellowship (18POST34030388). J.P.K. is supported by AHA Postdoctoral Fellowship (903306). A.F. was funded by Ermenegildo Zegna Founder’s Scholarship (2017) and by American Diabetes Association postdoctoral fellowship (1-19-PDF-043-RA). Y.G. is supported by Damon Runyon Cancer Research Foundation and Mark Foundation postdoctoral fellowship (DRG2424-21). R.T.N. was supported by a T32GM008042 grant to the UCLA-Caltech Medical Scientist Training Program. A.N. was supported by the NIDDK of the National Institutes of Health under Award Number T32DK007180. We thank all members of the Tontonoz, Tarling-Vallim, Edwards, Villanueva, Young and Bensinger laboratories at UCLA for useful advice and discussions and for sharing reagents and resources. We thank K. Williams, G. Su and staff at UCLA Lipidomics core for the lipidomics analysis. Confocal microscopy was performed at the California NanoSystems Institute of Advanced Light Microscopy/Spectroscopy Facility. We thank the Vector Core of the University of Michigan for AAV packaging. We thank J. Smothers and A. Radhakrishnan for the helpful suggestions about the ALOD4 protein purification. This work was supported by NIH grant R01 DK126779 and Fondation Leducq Transatlantic Network of Excellence (19CVD04). X.X. was supported by AHA Postdoctoral Fellowship (18POST34030388). J.P.K. is supported by AHA Postdoctoral Fellowship (903306). A.F. was funded by Ermenegildo Zegna Founder’s Scholarship (2017) and by American Diabetes Association postdoctoral fellowship (1-19-PDF-043-RA). Y.G. is supported by Damon Runyon Cancer Research Foundation and Mark Foundation postdoctoral fellowship (DRG2424-21). R.T.N. was supported by a T32GM008042 grant to the UCLA-Caltech Medical Scientist Training Program. A.N. was supported by the NIDDK of the National Institutes of Health under Award Number T32DK007180.
| Funders | Funder number |
|---|---|
| Mark Foundation for Cancer Research | DRG2424-21, T32GM008042 |
| UCLA-Caltech | |
| National Institutes of Health (NIH) | R01 DK126779, T32DK007180 |
| American Diabetes Association Inc | 1-19-PDF-043-RA |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| American the American Heart Association | 18POST34030388, 903306 |
| Damon Runyon Cancer Research Foundation | |
| University of California, Los Angeles | |
| Michigan Diabetes Research Center, University of Michigan | |
| Fondation Leducq | 19CVD04 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
- Physiology (medical)
- Cell Biology
