Ip3r-Grp75-Vdac and Relevant Ca2+ Signaling Regulate Dietary Palmitic Acid-Induced De Novo Lipogenesis by Mitochondria-Associated ER Membrane (MAM) Recruiting Seipin in Yellow Catfish

Yu-Feng Song; Zhen-Yu Bai; Xiao-Hong Lai; Zhi Luo; Christer Hogstrand

doi:10.1016/j.tjnut.2024.04.021

Ip3r-Grp75-Vdac and Relevant Ca²⁺ Signaling Regulate Dietary Palmitic Acid-Induced De Novo Lipogenesis by Mitochondria-Associated ER Membrane (MAM) Recruiting Seipin in Yellow Catfish

J Nutr. 2024 Apr 17:S0022-3166(24)00224-4. doi: 10.1016/j.tjnut.2024.04.021. Online ahead of print.

Authors

Yu-Feng Song¹, Zhen-Yu Bai², Xiao-Hong Lai², Zhi Luo³, Christer Hogstrand⁴

Affiliations

¹ Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China. Electronic address: syf880310@mail.hzau.edu.cn.
² Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China.
³ Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
⁴ Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Franklin-Wilkins Building, London, United Kingdom.

PMID: 38641205
DOI: 10.1016/j.tjnut.2024.04.021

Abstract

Background: The mitochondria-associated endoplasmic reticulum membrane (MAM) is the central hub for endoplasmic reticulum and mitochondria functional communication. It plays a crucial role in hepatic lipid homeostasis. However, even though MAM has been acknowledged to be rich in enzymes that contribute to lipid biosynthesis, no study has yet investigated the exact role of MAM on hepatic neutral lipid synthesis.

Objectives: To address these gaps, this study investigated the systemic control mechanisms of MAM on neutral lipids synthesis by recruiting seipin, focusing on the role of the inositol trisphosphate receptor-1,4,5(Ip3r)-75 kDa glucose-regulated protein (Grp75)-voltage-dependent anion channel (Vdac) complex and their relevant Ca²⁺ signaling in this process.

Methods: To this end, a model animal for lipid metabolism, yellow catfish (Pelteobagrus fulvidraco), were fed 6 different diets containing a range of palmitic acid (PA) concentrations from 0-150 g/kg in vivo for 10 wk. In vitro, experiments were also conducted to intercept the MAM-mediated Ca²⁺ signaling in isolated hepatocytes by transfecting them with si-mitochondrial calcium uniporter (mcu). Because mcu was placed in the inner mitochondrial membrane (IMM), si-mcu cannot disrupt MAM's structural integrity.

Results: 1. Hepatocellular MAM subproteome analysis indicated excessive dietary PA intake enhanced hepatic MAM structure joined by activating Ip3r-Grp75-Vdac complexes. 2. Dietary PA intake induced hepatic neutral lipid accumulation through MAM recruiting Seipin, which activated lipid droplet biogenesis. Our findings also revealed a previously unidentified mechanism whereby MAM-recruited seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca²⁺ signaling and not only MAM's structural integrity.

Conclusions: These results offer a novel insight into the MAM-recruited seipin in controlling hepatic lipid synthesis in a MAM structural integrity-dependent and Ca²⁺ signaling-dependent manner, highlighting the critical contribution of MAM in maintaining hepatic neutral lipid homeostasis.

Keywords: Ca(2+) signaling; Hepatic lipogenesis; Ip3r-Grp75-Vdac complex; Mitochondria-associated endoplasmic reticulum membrane (MAM); Seipin.