Fatty Acid Transport Protein 1 (FATP1) Localizes in Mitochondria in Mouse Skeletal Muscle and Regulates Lipid and Ketone Body Disposal

Abstract

FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and β-hydroxybutyrate levels were higher in FATP1- than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1- versus GFP-mice regardless of diet, and β-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from β-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids.

The blood–brain barrier and protein‐mediated fatty acid uptake: role of the blood–brain barrier as a metabolic barrier

“…), mitochondria (Schaffer and Lodish ; Guitart et al . ), and endoplasmic reticulum (Zhan et al . ).…”

“…Nonetheless, as illustrated herein, there is evidence that all three of these mechanisms occur within the microvessel endothelial cells comprising the BBB. some debate about where FATP1 is localized within the cell, including it being found at the plasma membrane (Schaffer and Lodish 1994;Stahl et al 2002), mitochondria (Schaffer and Lodish 1994;Guitart et al 2014), and endoplasmic reticulum (Zhan et al 2012). FATP1 also has acyl-CoA synthetase activity and use a wide range of fatty acids (16-24 carbons) as substrates (Coe et al 1999;Hall et al 2003).…”

Possible relationship between common genetic variation and white matter development in a pilot study of preterm infants

“…SLC27A1 (also known as fatty acid transport molecule 1, FATP1) is localized to mitochondria (Guitart et al. ), is involved in fatty acid transport across the blood–brain barrier (Mitchell et al. ) and has been considered as a therapeutic target for insulin resistance (Matsufuji et al.…”

“…PLIN1 regulates droplet formation in lipopolysaccharide-stimulated microglia (Khatchadourian et al 2012) and mutations have been linked to familial lypodistrophy and severe insulin resistance and T2DM (Kozusko et al 2015). SLC27A1 (also known as fatty acid transport molecule 1, FATP1) is localized to mitochondria (Guitart et al 2014), is involved in fatty acid transport across the blood-brain barrier (Mitchell et al 2011) and has been considered as a therapeutic target for insulin resistance (Matsufuji et al 2012). There are indications that AQP7 expression is associated with insulin resistance and obesity (Lebeck 2014), and missense mutations in humans result in a variety of neurological sequelae including severe hypotonia, psychomotor retardation and/or epilepsy as well as multisystem abnormalities (Goubau et al 2013).…”

Peer Review #1 of "Adipose tissues of MPC1± mice display altered lipid metabolism-related enzyme expression levels (v0.1)"

“…Echs1, a gene involved in fatty acid beta oxidation, regulates cellular ATP production (Zhu et al 2012). The fatps gene facilitates the uptake of very long-chain (VLCFA) and long-chain fatty acids (LCFA) (Guitart et al 2014).…”