Major Facilitator Superfamily Domain-Containing Protein 2a (MFSD2A) Has Roles in Body Growth, Motor Function, and Lipid Metabolism

Abstract

The metabolic adaptations to fasting in the liver are largely controlled by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα), where PPARα upregulates genes encoding the biochemical pathway for β-oxidation of fatty acids and ketogenesis. As part of an effort to identify and characterize nutritionally regulated genes that play physiological roles in the adaptation to fasting, we identified Major facilitator superfamily domain-containing protein 2a (Mfsd2a) as a fasting-induced gene regulated by both PPARα and glucagon signaling in the liver. MFSD2A is a cell-surface protein homologous to bacterial sodium-melibiose transporters. Hepatic expression and turnover of MFSD2A is acutely regulated by fasting/refeeding, but expression in the brain is constitutive. Relative to wildtype mice, gene-targeted Mfsd2a knockout mice are smaller, leaner, and have decreased serum, liver and brown adipose triglycerides. Mfsd2a knockout mice have normal liver lipid metabolism but increased whole body energy expenditure, likely due to increased β-oxidation in brown adipose tissue and significantly increased voluntary movement, but surprisingly exhibited a form of ataxia. Together, these results indicate that MFSD2A is a nutritionally regulated gene that plays myriad roles in body growth and development, motor function, and lipid metabolism. Moreover, these data suggest that the ligand(s) that are transported by MFSD2A play important roles in these physiological processes and await future identification.

Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development

“…1D). The two molecular weight species observed for Mfsd2a in the retina have been observed previously for Mfsd2a in liver and in overexpression studies in HEK293 cells and explained by alternative glycosylation (18,20). The single molecular weight species of Mfsd2a detected in RPE is similar to the molecular weight of Mfsd2a reported for brain (16).…”

“…8B). The eyeballs of LLTie2cre mice were smaller than LL control mice, a finding similar to Mfsd2a KO mice, and related to the severe microcephaly exhibited by both mouse models (16,20). Histological examination indicated that OS length relative to total photoreceptor length in 4-month-old LLTie2cre mice was comparable with LL control mice (Fig.…”

“…550274, Pharmingen); Mfsd2a (20); rhodopsin (catalog no. MAB5356, Chemicon/Millipore); ezrin (catalog no.…”

“…Animals-Mfsd2a KO mice were generated as described previously (20). Mfsd2a floxed mice (Mfsd2a tm1a(KOMP)Wtsi ) were purchased from KOMP Repository where the Mfsd2a exon 3 is floxed by two loxP sites.…”

Both maternal and offspring Elovl2 genotypes determine systemic DHA levels in perinatal mice

“…This is in line with previous results indicating that Mfsd2a is a nutritionally regulated gene that plays numerous roles in body growth and development, motor function, and lipid metabolism (56,57). Its expression in liver is found to be dependent on PPAR and glucagon signaling and is increased in liver upon food deprivation.…”