Major Facilitator Superfamily Domain-containing protein 2a is a novel PPAR-alpha target with roles in body growth, motor function, and lipid metabolism

Abstract

Understanding how the body switches between storing and burning energy is fundamental to our ability to better treat metabolic disease. The metabolic adaptations to fasting in the liver are largely controlled by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha), where PPARalpha upregulates genes encoding the biochemical pathway for beta-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 PPARalpha and glucagon signaling in the liver. Minimal existing literature describes MFSD2A as 1) homologous to bacterial sodium-melibiose transporters, 2) induced in brown adipose tissue by cold exposure and beta-adrenergic signaling, 3) important in syncytia formation in human placenta, 4) as a potential tumor suppressor, and 5) with a putative role in tunicamycin transport.;We have confirmed that MFSD2A is a doubly glycosylated, cell-surface protein. 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 (KO) mice are smaller, leaner, and have decreased serum, liver, and brown adipose triglycerides. About 50% of Mfsd2a KO mice die in early post-natal life, though they are developmentally normal and show minimal changes in placenta. The KO mice have normal liver lipid metabolism but increased whole-body energy expenditure, likely due to increased beta-oxidation in brown adipose tissue and significantly increased voluntary movement. Because of these two mechanisms, male KO mice are protected from diet-induced weight gain, despite developing hepatosteatosis and insulin resistance. While the lipid phenotypes are sexually dimorphic, both males and females exhibit smaller body size and neurologic changes, including forelimb clasping and ataxia. This is attributed to a loss of Purkinje cells in KO mice as well as changes to Purkinje cell firing. Rescue of these phenotypes through transgenic expression of MFSD2A in the brain was attempted unsuccessfully.;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. Whether the phenotypes observed are due to central or peripheral roles of MFSD2A remains to be determined. Moreover, these data suggest that the ligand or ligands that MFSD2A transports play important roles in these physiological processes and await future identification.