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當心 肝細胞溶血磷脂抵抗脂肪肝來
當心 肝細胞溶血磷脂抵抗脂肪肝來當心 肝細胞溶血磷脂抵抗脂肪肝來
A healthy liver can metabolize lipids in specific pathways, primarily involving the uptake of circulating fatty acids, de novo lipogenesis, disposing lipids through oxidation (in the mitochondria, peroxisomes and cytochromes), and exporting lipids as minuscule particles. When the accumulation of lipid in liver cells surpassed their disposal capacity, large lipid drops can form and are difficult for the cell to breakdown and eliminate. To maintain efficient lipid metabolism, phospholipids, a main component of cell membranes, are in constant demand and undergo rapid turnover in cells. This process resembles tearing down old walls in a house and immediately constructing new ones, necessitating the participation of many commanders (pathway regulators). Lysophospholipids are one of the regulators. Lysophospholipids are a group of highly bioactive intermediate cell products that play a critical role in maintaining cellular abundancy of phospholipids, facilitating the formation of tiny lipid particles, and preventing the formation of large lipid drops. However, a challenge arises: lysophospholipids are partially water soluble and primarily present in body fluids, such as blood, how can they penetrate the highly hydrophobic cell membranes to exert their functions?
Liver cells are sophisticated and swift operators. They know how to make gateways in the walls to allow essential molecules in. In scientific phrase, liver cells can express specific transporter molecules on the cell membranes. One of these transporters, with a quite complicated name, major facilitator superfamily domain containing 2A (Mfsd2a), functions as gateways for lysophospholipids to enter liver cells. Mfsd2a was identified by the David L. Silver’s team from Duke-NUS Medical School in Singapore in 2012. Mfsd2a is mainly distributed in blood–brain barrier, facilitating the transportation of DHA into brain cells. It was not considered to be a fundamental component of healthy livers. However, researchers observed that the expression of Mfsd2a increased substantively in patients with fatty livers or in mice challenged with high-fat diet. When Mfsd2a was selectively deleted from mouse livers, those unlucky rodents developed severe steatohepatitis and fibrosis after feeding high-fat diet for 2~16 weeks, associated with reduced beneficial hepatic phospholipids. Despite Mfsd2a’s potent role in transporting lysophospholipids to assist liver cells to “return to homeostasis”, its functions require the regulation from glucocorticoid receptor (dexamethasone is the most common glucocorticoid).
These significant research findings were published in the Journal of Clinical Investigation on September 1, 2023, under the title of " Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition” (https://www.jci.org/articles/view/171267). The journal of Clinical Investigation is renowned for its stringent selection process, long review time, and numerous review comments. However, this groundbreaking discovery, supported by a solid amount of high-quality clinical data, was selected as the cover story of the 133rd issue, owing to its novelty and inspiration.
Unlike its central character in brain cells where DHA transportation is constantly required, Mfsd2a acts more like temporary emergency gateways in liver cells. These gateways are scarce under normal situations but are swiftly “constructed” when liver cells encounter overnutrition. Moreover, Mfsd2a was exclusively expressed on the basolateral side of periportal liver cells, meaning the gateways open to the very front line to receive nutrients from blood vessels. The Silver team has also proposed the mechanism by which Mfsd2a transports lysophospholipids into cells in a Na+-dependent manner: Mfsd2a maintains a V-shape structure and the outward-facing configuration allows it to receive lysophospholipids from the bloodstream. Once lysophospholipids are inserted into the hydrophobic cleft of Mfsd2a, the gateways undergo a conformational change from outward-facing to inward-facing. As a result, lysophospholipids are transferred from the outer leaflet to the inner leaflet and successfully transported to the interior of liver cells.
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Liver cells are sophisticated and swift operators. They know how to make gateways in the walls to allow essential molecules in. In scientific phrase, liver cells can express specific transporter molecules on the cell membranes. One of these transporters, with a quite complicated name, major facilitator superfamily domain containing 2A (Mfsd2a), functions as gateways for lysophospholipids to enter liver cells. Mfsd2a was identified by the David L. Silver’s team from Duke-NUS Medical School in Singapore in 2012. Mfsd2a is mainly distributed in blood–brain barrier, facilitating the transportation of DHA into brain cells. It was not considered to be a fundamental component of healthy livers. However, researchers observed that the expression of Mfsd2a increased substantively in patients with fatty livers or in mice challenged with high-fat diet. When Mfsd2a was selectively deleted from mouse livers, those unlucky rodents developed severe steatohepatitis and fibrosis after feeding high-fat diet for 2~16 weeks, associated with reduced beneficial hepatic phospholipids. Despite Mfsd2a’s potent role in transporting lysophospholipids to assist liver cells to “return to homeostasis”, its functions require the regulation from glucocorticoid receptor (dexamethasone is the most common glucocorticoid).
These significant research findings were published in the Journal of Clinical Investigation on September 1, 2023, under the title of " Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition” (https://www.jci.org/articles/view/171267). The journal of Clinical Investigation is renowned for its stringent selection process, long review time, and numerous review comments. However, this groundbreaking discovery, supported by a solid amount of high-quality clinical data, was selected as the cover story of the 133rd issue, owing to its novelty and inspiration.
Unlike its central character in brain cells where DHA transportation is constantly required, Mfsd2a acts more like temporary emergency gateways in liver cells. These gateways are scarce under normal situations but are swiftly “constructed” when liver cells encounter overnutrition. Moreover, Mfsd2a was exclusively expressed on the basolateral side of periportal liver cells, meaning the gateways open to the very front line to receive nutrients from blood vessels. The Silver team has also proposed the mechanism by which Mfsd2a transports lysophospholipids into cells in a Na+-dependent manner: Mfsd2a maintains a V-shape structure and the outward-facing configuration allows it to receive lysophospholipids from the bloodstream. Once lysophospholipids are inserted into the hydrophobic cleft of Mfsd2a, the gateways undergo a conformational change from outward-facing to inward-facing. As a result, lysophospholipids are transferred from the outer leaflet to the inner leaflet and successfully transported to the interior of liver cells.
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