Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease

Abstract

Long-chain fatty acids and lipids serve a wide variety of functions in mammalian homeostasis, particularly in the formation and dynamic properties of biological membranes and as fuels for energy production in tissues such as heart and skeletal muscle. On the other hand, long-chain fatty acid metabolites may exert toxic effects on cellular functions and cause cell injury. Therefore, fatty acid uptake into the cell and intracellular handling need to be carefully controlled. In the last few years, our knowledge of the regulation of cellular fatty acid uptake has dramatically increased. Notably, fatty acid uptake was found to occur by a mechanism that resembles that of cellular glucose uptake. Thus, following an acute stimulus, particularly insulin or muscle contraction, specific fatty acid transporters translocate from intracellular stores to the plasma membrane to facilitate fatty acid uptake, just as these same stimuli recruit glucose transporters to increase glucose uptake. This regulatory mechanism is important to clear lipids from the circulation postprandially and to rapidly facilitate substrate provision when the metabolic demands of heart and muscle are increased by contractile activity. Studies in both humans and animal models have implicated fatty acid transporters in the pathogenesis of diseases such as the progression of obesity to insulin resistance and type 2 diabetes. As a result, membrane fatty acid transporters are now being regarded as a promising therapeutic target to redirect lipid fluxes in the body in an organ-specific fashion.

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

“…This difference in liver lipid accumulation may partly explain the maintained glucose tolerance and insulin action in the HFD-fed BALB/c mice and is potentially due to lower rates of fatty acid uptake in BALB/c liver. In BALB/c mice, the levels of FATP2 and FATP4, which are the most abundant fatty acid transporters in liver [36], remained either unchanged (FATP2) or were decreased (FATP4), whereas in most other strains these transporters increased when fed an HFD. The BALB/c mice phenotype of increased fat mass but normal glucose tolerance and insulin action seems similar to the recently described metabolically healthy obese (MHO) humans.…”

Protein Kinase D1 Is Essential for Contraction-induced Glucose Uptake but Is Not Involved in Fatty Acid Uptake into Cardiomyocytes

“…On the other hand, AMPK activation is involved in both GLUT4 and CD36 translocation in cardiomyocytes. First, in rat cardiomyocytes, AMPK-activating stimuli induce translocation of both GLUT4 and CD36 (1,3), and in cardiomyocytes from dominant-negative AMPK expressing mice (17), both contraction-induced glucose and LCFA uptake are abolished (6). Moreover, in the present study, we observed that in AMPK-silenced HL1 cells and in cardiomyocytes from …”

“…Alterations in contraction are an important denominator of cardiac substrate utilization. Increased contraction enhances the demands for glucose and LCFA, and accordingly, GLUT4 and CD36 have been found to translocate to the sarcolemma under this condition (1,3).…”

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

“…The present study confirmed that expression of the FAS gene (de novo fatty acid synthesis) was largely unchanged; accordingly, the supply of de novo synthesis of palmitic acid may not be affected by fibrate treatments. On the other hand, supply of fatty acids from the circulation to hepatocytes is most likely to be increased by fibrates because the expression of the FAT/CD36 gene, a main fatty acid transporter in hepatocytes (32), was strikingly upregulated and that of FATP2 was significantly augmented by fibrates. The current study showed that ACSL3 was significantly upregulated by fibrates.…”