Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis

Xu Xiao; John Paul Kennelly; Alessandra Ferrari; Bethan L Clifford; Emily Whang; Yajing Gao; Kevin Qian; Jaspreet Sandhu; Kelsey E Jarrett; Madelaine C Brearley-Sholto; Alexander Nguyen; Rohith T Nagari; Min Sub Lee; Sicheng Zhang; Thomas A Weston; Stephen G Young; Steven J Bensinger; Claudio J Villanueva; Thomas Q de Aguiar Vallim; Peter Tontonoz

doi:10.1038/s42255-022-00722-6

Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis

Nat Metab. 2023 Jan;5(1):165-181. doi: 10.1038/s42255-022-00722-6. Epub 2023 Jan 16.

Authors

Xu Xiao^#^{1

2}, John Paul Kennelly^#^{1

2}, Alessandra Ferrari^{1

2}, Bethan L Clifford³, Emily Whang⁴, Yajing Gao^{1

2}, Kevin Qian^{1

2}, Jaspreet Sandhu^{1

5}, Kelsey E Jarrett³, Madelaine C Brearley-Sholto³, Alexander Nguyen^{1

6}, Rohith T Nagari^{1

2}, Min Sub Lee⁷, Sicheng Zhang⁸, Thomas A Weston⁹, Stephen G Young^{9

10}, Steven J Bensinger^{7

11}, Claudio J Villanueva⁸, Thomas Q de Aguiar Vallim^{2

3

5

12}, Peter Tontonoz^{13

14}

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Pediatric Gastroenterology, Hepatology and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹² Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles, Los Angeles, CA, USA.
¹³ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA. ptontonoz@mednet.ucla.edu.
¹⁴ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. ptontonoz@mednet.ucla.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biological Transport / physiology
Cholesterol* / metabolism
Fatty Acids / metabolism
Homeostasis
Liver* / metabolism

Substances

Cholesterol
Fatty Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding