Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition
The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis-like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools - processes that are critical for protecting the liver from excess dietary fat.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
|---|---|
| Enthalten in: |
The Journal of clinical investigation - 133(2023), 17 vom: 01. Sept. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Chin, Cheen Fei [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Dietary Fats |
|---|
| Anmerkungen: |
Date Completed 04.09.2023 Date Revised 15.09.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1172/JCI171267 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359635407 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359635407 | ||
| 003 | DE-627 | ||
| 005 | 20231226081310.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1172/JCI171267 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1198.xml |
| 035 | |a (DE-627)NLM359635407 | ||
| 035 | |a (NLM)37463052 | ||
| 035 | |a (PII)e171267 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Chin, Cheen Fei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.09.2023 | ||
| 500 | |a Date Revised 15.09.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis-like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools - processes that are critical for protecting the liver from excess dietary fat | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Hepatology | |
| 650 | 4 | |a Homeostasis | |
| 650 | 4 | |a Metabolism | |
| 650 | 4 | |a Mouse models | |
| 650 | 4 | |a Transport | |
| 650 | 7 | |a Phospholipids |2 NLM | |
| 650 | 7 | |a Lysophospholipids |2 NLM | |
| 650 | 7 | |a Phosphatidylcholines |2 NLM | |
| 650 | 7 | |a Dietary Fats |2 NLM | |
| 700 | 1 | |a Galam, Dwight LA |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Bryan C |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Bernice H |e verfasserin |4 aut | |
| 700 | 1 | |a Chua, Geok-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Loke, Randy Yj |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Yen Ching |e verfasserin |4 aut | |
| 700 | 1 | |a Wenk, Markus R |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Miao-Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Leow, Wei-Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Goh, George Bb |e verfasserin |4 aut | |
| 700 | 1 | |a Torta, Federico |e verfasserin |4 aut | |
| 700 | 1 | |a Silver, David L |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of clinical investigation |d 1924 |g 133(2023), 17 vom: 01. Sept. |w (DE-627)NLM000005487 |x 1558-8238 |7 nnns |
| 773 | 1 | 8 | |g volume:133 |g year:2023 |g number:17 |g day:01 |g month:09 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/JCI171267 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 133 |j 2023 |e 17 |b 01 |c 09 | ||