Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis

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

doi:10.1038/s42255-022-00722-6

Cited by 33 publications

(25 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies showed that in macrophages ( 33 ) and hepatocytes ( 28 ) Asters specifically recognize the accessible pool of PM cholesterol ( 34 , 35 ). To prove that Asters transfer accessible cholesterol from the PM to ER in intestinal epithelial cells, we stained WT and Aster-B/C KO enteroids with ALOD4, a bacterial peptide that selectively binds to accessible cholesterol.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Ferrari,

Whang,

Xiao

et al. 2023

Science

Self Cite

View full text Add to dashboard Cite

Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The role of nonvesicular cholesterol transport in cell function is highly cell-type specific. In mice, Aster-B is required for CE storage and corticosteroid synthesis in the adrenal cortex ( 25 ), whereas Aster-C is important for hepatic reverse cholesterol transport ( 28 ).…”

mentioning

confidence: 99%

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Ferrari,

Whang,

Xiao

et al. 2023

Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the protein lacks ATPase activity and should not raise the chemical activity of membrane cholesterol on its own. It is therefore of interest that it increases the binding of cytolysins to plasma membranes and their susceptibility to cholesterol oxidase ( 41 , 137 , 143 , 144 , 145 ). Perhaps this is because SR-BI boosts the activity of plasma membrane cholesterol by facilitating the uptake of the sterol from plasma lipoproteins ( 136 , 145 ).…”

Section: Sr-bimentioning

confidence: 99%

Is reverse cholesterol transport regulated by active cholesterol?

Steck

Lange

2023

Journal of Lipid Research

View full text Add to dashboard Cite

“…Therefore, the trafficking of PM cholesterol to intracellular organelles is tightly controlled to maintain cellular homeostasis. A recently identified family of ER-resident proteins called Asters (Aster-A, -B, and -C) form membrane-membrane contact sites to facilitate the transfer cholesterol away from the PM ( Sandhu et al, 2018 ; Naito et al, 2019 ; Ferrari et al, 2020 ; Ferrari et al, 2023 ; Xiao et al, 2023 ). Aster-B was first described as a liver X receptor (LXR)-stimulated cholesterol transporter that facilitates PM-to-ER sterol transfer for cholesterol ester (CE) storage in the adrenal gland ( Sandhu et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…Aster-B was first described as a liver X receptor (LXR)-stimulated cholesterol transporter that facilitates PM-to-ER sterol transfer for cholesterol ester (CE) storage in the adrenal gland ( Sandhu et al, 2018 ). More recently, Aster-C was found to be a direct transcriptional target gene for the farnesoid X receptor (FXR) in the liver where it plays a role in reverse cholesterol transport (RCT) ( Xiao et al, 2023 ). Although there is emerging evidence of functional redundancy in some tissues, all three Asters (A, B, and C) have been implicated in both intestinal and hepatic cholesterol trafficking under certain conditions of fasting and re-feeding ( Ferrari et al, 2023 ; Xiao et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

The nonvesicular sterol transporter Aster-C plays a minor role in whole body cholesterol balance

Banerjee,

Hohe,

Cao

et al. 2024

Front. Physiol.

View full text Add to dashboard Cite

Introduction:The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions.Method:Age-matched Gramd1c+/+ and Gramd1c−/− mice were fed either low (0.02%, wt/wt) or high (0.2%, wt/wt) dietarycholesterol and levels of sterol-derived metabolites were assessed in the feces, liver, and plasma.Results:Compared to wild type controls (Gramd1c+/+) mice, mice lackingGramd1c (Gramd1c−/−) have no significant alterations in fecal, liver, or plasma cholesterol. Given the potential role for Aster C in modulating cholesterol metabolism in diverse tissues, we quantified levels of cholesterol metabolites such as bile acids, oxysterols, and steroid hormones. Compared to Gramd1c+/+ controls, Gramd1c−/− mice had modestly reduced levels of select bile acid species and elevated cortisol levels, only under low dietary cholesterol conditions. However, the vast majority of bile acids, oxysterols, and steroid hormones were unaltered in Gramd1c−/− mice. Bulk RNA sequencing in the liver showed that Gramd1c−/− mice did not exhibit alterations in sterol-sensitive genes, but instead showed altered expression of genes in major urinary protein and cytochrome P450 (CYP) families only under low dietary cholesterol conditions.Discussion:Collectively, these data indicate nominal effects of Aster-C on whole body cholesterol transport and metabolism under divergent dietary cholesterol conditions. These results strongly suggest that Aster-C alone is not sufficient to control whole body cholesterol balance, but can modestly impact circulating cortisol and bile acid levels when dietary cholesterol is limited.

show abstract

Hepatic nonvesicular cholesterol transport is critical for systemic lipid homeostasis

Cited by 33 publications

References 55 publications

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

Is reverse cholesterol transport regulated by active cholesterol?

The nonvesicular sterol transporter Aster-C plays a minor role in whole body cholesterol balance

Contact Info

Product

Resources

About