The pathogenetic role of impaired fatty acid trapping by adipocytes in generating the pleiotropic features of hyperapoB

Abstract

HyperapoB is the commonest dyslipoproteinaemia associated with coronary disease [1,2] and is characterized by an increased LDL particle number due to increased secretion of B100 lipoproteins by the liver [3]. The first feature of hyperapoB to be recognized was the elevated LDL particle number, many of which are smaller and denser than normal [4]. In reality, though, the metabolism of all the lipoprotein classes is demonstrably abnormal.At the onset, however, it must be appreciated that hyperapoB is a phenotype, not a genotype, and there are multiple causes which produce increased hepatic secretion of B100 lipoprotein particles. The focus in this review, however, will be to outline how a reduced rate of fatty acid trapping by adipocytes can produce the pleiotropic features which characterize hyperapoB. At the end of this line of reasoning lies the conclusion that faults in fatty acid metabolism, not errors in the LDL pathway, are the commonest causes for the atherogenic dyslipoproteinaemias seen clinically.The features of hyperapoB to be explicated are: 1) increased hepatic VLDL secretion; 2) increased LDL particle number; 3) smaller denser LDL particles; 4) reduced HDL cholesterol levels; 4) postprandial hyperlipaemia with accumulation of triglyceride-rich remnants; 5) elevated plasma non-esterified fatty acid levels (NEFA); and 6) insulin resistance. Regulation of the rate of fatty acid storage by adipocytesThe normal sequence involved in the uptake by adipocytes of fatty acids released from chylomicrons can be summarized as follows: chylomicrons attach to endothelial cells and the triglyceride within them is rapidly hydrolysed by lipoprotein lipase (LPL) [5]. The rate at which chylomicron triglyceride hydrolysis proceeds is determined by the number of LPL molecules involved and by the rate at which the NEFA which are generated are removed from the capillary microenvironment.The NEFA which are liberated from the chylomicrons can enter the adipocyte to be trapped within it as triglyceride. Alternatively, they may bind to albumin, leave the capillary, and enter the general circulation. The proportion of NEFA released from chylomicrons which enter adipocytes is necessarily the reciprocal of the proportion which are not trapped by adipocytes and which then leave the microenvironment. Under normal circumstance, the proportions are about equal [6]. The proportion of NEFA which are trapped by adipocytes is determined by their rate of triglyceride synthesis, the major determinant of which is the acylation stimulating protein (ASP) pathway [7].ASP is the product of the ASP pathway and, as just noted, is the major determinant of the rate of triglyceride synthesis within adipocytes. The major features of the pathway are described elsewhere [8]. In brief, human adipocytes synthesize and secrete the three proteins of the alternate complement pathway which interact to form a 77 amino terminal fragment of C3, the terminal arginine of which is removed by carboxypeptidases to produce ASP. ASP then interacts specifically with a ...

Apolipoprotein B: a predictor of inflammatory status in postmenopausal overweight and obese women

“…Another plausible mechanism by which plasma ApoB may predict inflammation is its ability to reflect the efficiency of fatty acid storage in adipose tissue [29]. Several types of fatty acids, like omega-6 [30], trans [31,32] and saturated fatty acids [32], have been shown to induce endothelial dysfunction and increased plasma concentration of CRP, IL-8, TNF-α, TNF-α-R2, adhesion molecules and IL-6.…”

In VivoModulation of Plasma Free Fatty Acids in Patients with Familial Combined Hyperlipidemia Using Lipid-Lowering Medication

“…In FCHL patients, impaired ASP action has been held responsible for decreased uptake of postprandial FFA and consequently increased postprandial FFA flux to liver and VLDL overproduction, as seen in FCHL (30,31). The slightly higher fasting C3 concentrations, the precursor of ASP, in FCHL patients supports the theory of impaired ASP action (31). The slightly higher fasting C3 concentrations, the precursor of ASP, in FCHL patients supports the theory of impaired ASP action (31).…”

Plasma acylation stimulating protein (ASP) as a predictor of impaired cellular biological response to ASP in patients with hyperapoB

“…A recent study demonstrates that ASP increases in the venous effluent of a subcutaneous adipose tissue bed post-prandially [23]. Our hypothesis is that a reduced ASP receptor level results in reduced efficiency of fatty acid trapping by adipocytes in the post-prandial period [19]. Moreover, release of ASP by adipocytes increased markedly during the second half of the post-prandial period, during the marked increase in TG clearance and tissue uptake of fatty acid that occurred at that time.…”

“…Notwithstanding the elevated free fatty acids, hormonesensitive lipase-mediated release of adipose tissue free fatty acids is not increased but, in fact, is slightly decreased [18]. Based on these results we have postulated that the fundamental metabolic fault, in at least a subset of these patients, is a defect in the efficiency with which fatty acids are stored in adipocytes [19]. In support of this hypothesis, our initial studies in human skin fibroblasts in hyperapoB subjects demonstrated a reduced response to ASP stimulation of TGS in some, but not all, subjects [8].…”

“…Finally, the data demonstrated a significant relationship between release of ASP and fatty acid uptake by adipocytes. Our hypothesis is that a reduced ASP receptor level results in reduced efficiency of fatty acid trapping by adipocytes in the post-prandial period [19]. A reduced rate of fatty acid uptake by adipocytes will result in increased capillary fatty acid concentrations that would inhibit lipoprotein lipase activity and diminish TG clearance from plasma [34].…”