Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways

Abstract

Cells obtain FAs either from LPL-catalyzed hydrolysis of lipoprotein triglyceride or from unesterified FFAs associated with albumin. LPL also influences uptake of esterified lipids such as cholesteryl and retinyl esters that are not hydrolyzed in the plasma. This process might not involve LPL enzymatic activity. LPL is regulated by feeding/ fasting, insulin, and exercise. Although a number of molecules may affect cellular uptake of FFAs, the best characterized is CD36. Genetic deletion of this multiligand receptor reduces FFA uptake into skeletal muscle, heart, and adipose tissue, and impairs intestinal chylomicron production and clearance of lipoproteins from the blood.CD36 is regulated by some of the same factors that regulate LPL, including insulin, muscle contraction, and fasting, in part, via ubiquitination. LPL and CD36 actions in various tissues coordinate biodistribution of fat-derived calories. There are several pathways that allow the uptake of circulating lipids into cells. Cell surface receptors mediate the uptake of whole lipoproteins. FA uptake is more similar to that of the other major blood nutrient, glucose. Unlike glucose, which is water soluble, FAs are either associated with albumin, so-called free (FFA), or are esterified as a component of triglycerides (TGs), phospholipids, and esterified cholesterol. Esterified FAs within VLDL and chylomicrons comprise .90% of blood FAs. Nonetheless, the rapid plasma turnover of FFA has the potential to supply large amounts of energy to tissues. LIPID UPTAKE VIA THE LIPOLYSIS PATHWAYThe importance of the lipolysis reaction in the catabolism of TG-rich lipoproteins was shown more than 50 years ago by the discovery that intravenous heparin injection leads to the release of LPL into the plasma and reduces postprandial lipemia. Subsequent studies established that LPL is robustly expressed in tissues like adipose and muscle that require large influxes of FAs for storage or energy and that LPL is the primary enzyme responsible for chylomicron-and VLDL-TG lipolysis. However, several questions on the role of this enzyme in fuel partitioning and tissue lipid uptake, its regulation, and its importance for vascular biology remained to be answered.Genetic modulation of LPL protein and its sites of expression have partially elucidated how LPL affects physiology and has confirmed prior in vitro studies. Although humans with LPL deficiency develop severe hypertriglyceridemia and are at risk for pancreatitis, mice with spontaneous or genetic loss of LPL die within 24 h of birth. Prior to death, LPL-deficient mice develop hypoglycemia, a process that is partially abrogated by ketone body production via LPL expression in the liver (1). In contrast, tissuespecific overexpression of LPL in skeletal muscle and liver increased cellular stores of TG and probably other lipids and led to insulin resistance (2). Loss of LPL in adipose tissue and its overexpression in skeletal muscle reduced adipose development when these mice were crossed onto the obesity ob/ob background ...

Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

“…However, our study showed that HFD exerts minor effects on Irs1 and Glut4 mRNA in SKM compared with the change in WAT, agreeing with a previous report (Anai et al 1999). NEFA uptake by SKM is controlled by both circulating lipid levels and specific transporters, particularly LPL and FAT/CD36 (Koonen et al 2005, Goldberg et al 2009). Here, we found upregulated LPL and FAT/CD36 expression in SKM and IMCL deposition in HFD-fed CTR and CPO mice, with stronger effects in CPO-HFD mice.…”

Ractopamine effect on lipid metabolism and GLUT4 amount of finishing pigs

“…Evaluating the activity of this enzyme can be a valid tool for the study of the anabolic fat pathway, especially in adipose tissue (8). Based on the effects of catecholamines on LPL activity in adipose and muscle tissue, with a decrease and increase, respectively, found by Fonseca-Alaniz et al (9) and Goldberg et al (10), it was expected that swine LPL activity after RAC supplementation could also provide the same change; however, this effect was not observed, probably because RAC does not act directly on the LPL activity of pigs. Another valid parameter for the study of the anabolic pathway, FAS, was also evaluated in this experiment.…”

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

“…The free fatty acids can then be captured by cellular fatty acid transporters (CD36 and SLC27A family members) into the tumor cells. 43 In a recent study, we found that LPL is upregulated in human HCC samples; and high expression of LPL is associated with poor prognosis. 44 In human HCC cell lines, silencing FASN or LPL or culturing the cells in lipoprotein-deficient medium led to significantly decreased cell proliferation.…”