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Merck

Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis.

Nature metabolism (2023-01-17)
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
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.

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Sigma-Aldrich
Anti-actina, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Atglistatin, ≥98% (HPLC)