Biology subjects

Kennelly, J. P.

Publications and source records attributed to Kennelly, J. P..

2 recordsLinked to original sources

bioRxiv2023

Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence SummaryIdentification of a targetable pathway for regulation of dietary cholesterol absorption

physiology↗

bioRxiv2023

Polarized Mechanosensitive Signaling Domains Protect Arterial Endothelial Cells Against Inflammation

Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, which supports an anti-inflammatory phenotype that protects them from atherosclerosis. High laminar shear stress also supports flow-aligned cell elongation and front-rear polarity, but whether this is required for athero-protective signaling is unclear. Here, we show that Caveolin-1-rich microdomains become polarized at the downstream end of ECs exposed to continuous high laminar flow. These microdomains are characterized by higher membrane rigidity, filamentous actin (F-actin) and lipid accumulation. Transient receptor potential vanilloid-type 4 (Trpv4) ion channels, while ubiquitously expressed, mediate localized Ca2+ entry at these microdomains where they physically interact with clustered Caveolin-1. The resultant focal bursts in Ca2+ activate the anti-inflammatory factor endothelial nitric oxide synthase (eNOS) within the confines of these domains. Importantly, we find that signaling at these domains requires both cell body elongation and sustained flow. Finally, Trpv4 signaling at these domains is necessary and sufficient to suppress inflammatory gene expression. Our work reveals a novel polarized mechanosensitive signaling hub that induces an anti-inflammatory response in arterial ECs exposed to high laminar shear stress.

cell biology↗