Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids.

Ayumi Kanatani,Keisuke Yanagida,Yoshiko Iizuka,Katsuyuki Nagata,Takao Shimizu,Megumi Yasuda,Fumie Hamano,Tadashi Okamura,Hideo Shindou,Daisuke Hishikawa

doi:10.1016/j.isci.2020.101495

Abstract

SummaryPolyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), play fundamental roles in mammalian physiology. Although PUFA imbalance causes various disorders, mechanisms of the regulation of their systemic levels are poorly understood. Here, we report that hepatic DHA-containing phospholipids (DHA-PLs) determine the systemic levels of PUFAs through the SREBP1-mediated transcriptional program. We demonstrated that liver-specific deletion of Agpat3 leads to a decrease of DHA-PLs and a compensatory increase of ARA-PLs not only in the liver but also in other tissues including the brain. Together with recent findings that plasma lysophosphatidylcholine (lysoPC) is the major source of brain DHA, our results indicate that hepatic AGPAT3 contributes to brain DHA accumulation by supplying DHA-PLs as precursors of DHA-lysoPC. Furthermore, dietary fish oil-mediated suppression of hepatic PUFA biosynthetic program was blunted in liver-specific Agpat3 deletion. Our findings highlight the central role of hepatic DHA-PLs as the molecular rheostat for systemic homeostasis of PUFAs.

Highlights

Recent studies have shown that besides their quantity, the qualities of fatty acids are involved in various human diseases, including metabolic syndrome, inflammatory diseases, and neuronal diseases (Bazinet and Laye, 2014; Estadella et al, 2013)
We demonstrated that liver-specific deletion of Agpat3 leads to a decrease of docosahexaenoic acid (DHA)-PLs and a compensatory increase of arachidonic acid (ARA)-PLs in the liver and in other tissues including the brain
Together with recent findings that plasma lysophosphatidylcholine is the major source of brain DHA, our results indicate that hepatic AGPAT3 contributes to brain DHA accumulation by supplying DHA-containing phospholipids (DHA-PLs) as precursors of DHA-lysoPC

Summary

Introduction

Recent studies have shown that besides their quantity, the qualities of fatty acids (e.g., saturated fatty acid toxicity and omega-3/omega-6 fatty acid balance) are involved in various human diseases, including metabolic syndrome, inflammatory diseases, and neuronal diseases (Bazinet and Laye, 2014; Estadella et al, 2013). For the syntheses from precursor fatty acids, both DHA and ARA require a number of common enzymes, namely, fatty acid desaturase 1 (FADS1), FADS2, and elongation of very long fatty acid protein-5 (ELOVL5) (Jalil et al, 2019). In the case of PUFAs with >22 carbon chains, such as DHA, an additional enzyme, ELOVL2, is required (Jalil et al, 2019).

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