Cholesterol trafficking in the cell is a key event in the control of cellular cholesterol homeostasis. Given the role of endoplasmic reticulum (ER) as the intracellular cholesterol sensor, comprehending the mechanisms involved in the delivery of exogenous cholesterol to the ER is crucial. Our research identified a family of proteins called Aster/Gramd1, which participate in non-vesicular cholesterol transport from the plasma membrane to the ER. We recently reported a role of these protein in the absorption of diet-derived cholesterol. 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 was unknown. We found that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes. These proteins cooperate with NPC1L1, which initially deposits cholesterol into the apical membrane, thereby increasing the local pool of accessible cholesterol. This event engages Aster-B and -C, that facilitate the movement of cholesterol to ER, where it undergoes esterification and subsequential incorporation into chylomicrons. The recruitment of Asters to membranes necessitates interaction with anionic phospholipids in the plasma membrane. This raises intriguing questions about the interplay between membrane phospholipid remodeling and the regulation of intracellular cholesterol trafficking.
The nutrient-sensing role of circadian clock in fat and muscle
The circadian clock is entrained by metabolic cues and exerts pervasive temporal control in metabolic processes. The intricate interplay between circadian clock with nutrient signals orchestrates homeostasis. Our research focuses on deciphering the molecular and signaling pathways underlying tissue-intrinsic clocks circuits in driving metabolic tissue functional capacity. Recent studies uncovered the nutrient-sensing role of clock that governs metabolic substrate metabolism. Mechanistic interrogations of clock modulation of nutrient metabolism in adipose tissue and skeletal muscle will be discussed, together with our recent foray into targeting these mechanisms for disease applications.