ASP enhances in situ lipoprotein lipase activity by increasing fatty acid trapping in adipocytes

Abstract

Dietary fat circulates in the blood in the form of triglyceride (TG)-rich lipoproteins (chylomicrons), which contain an inner core of 80-95% TG (1). Postprandially, plasma TG increases 2-2.5 times above fasting levels (2, 3) and is rapidly cleared from the plasma by the efficient coupling of two events. The first involves hydrolysis by lipoprotein lipase (LPL), and the second involves uptake and metabolic disposition by local tissue. LPL is situated principally in skeletal muscle and white adipose tissue (WAT). In skeletal muscle, the great majority of nonesterified fatty acids (NEFAs) are oxidized, whereas in WAT, they are esterified to form TG [for review, see ref. (4)].LPL exerts its lipolytic action while attached to the endothelial glycocalyx (5). LPL is synthesized and secreted from underlying parenchymal cells, mainly adipose and muscle tissue, and is then translocated to the endothelial apical surface (6). Studies of factors affecting LPL activity in WAT have focused primarily on the synthesis and secretion of LPL from the adipocytes. Insulin is a major promoter of LPL activity in that it causes both synthesis and secretion to increase. In vitro studies of murine 3T3-L1 cells have shown that insulin increases LPL activity through an increase in protein synthesis, dimerization, cellular secretion, and increased cell surface-associated mass (7-10). The effects of insulin are both time-and concentrationdependent (9, 10). Furthermore, the release of LPL from adipocytes is enhanced by an endothelial cell-secreted factor that is in turn insulin-dependent (10).The conventional view is that LPL activity in WAT is the rate-limiting step in the hydrolysis of TG-rich lipoproteins and the uptake of derived NEFAs (11). In fact, this has not always been supported by in vivo findings. In a study examining the effect of epinephrine on LPL activity in humans, the extraction of plasma TG across a subcutaneous WAT bed was increased with epinephrine infusion, indicating an increase in WAT LPL activity. However, LPLderived NEFAs were not taken up into WAT but released into the circulation (12). The authors concluded that the coordinated reciprocal regulation of NEFA influx and NEFA efflux (resulting from the activation of hormone sensitive lipase (HSL) by epinephrine) is an essential de-

Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia

“…15,25 This effect on fatty acid esterification occurs downstream of lipoprotein lipase action on chylomicrons/verylow-density lipoprotein and is independent of lipoprotein lipase. 13 These ASP functional effects are dependent on the presence of C5L2 as demonstrated recently. 18 In the present study, the cellular response to ASP of the three family members was compared with that of cells derived from a subset of the study subjects described in Table 1, which included: (1) control subjects (nϭ6) who had normal apoB and normal ASP plasma levels and (2) hyperapoB subjects with normal (nϭ6) or increased (nϭ8) plasma ASP levels.…”

“…ASP binds to adipocytes and preadipocytes, promotes triglyceride synthesis through stimulation of both glucose transport and fatty acid esterification, 11,12 indirectly enhancing the action of lipoprotein lipase. 13 Patients with coronary heart disease have increased plasma ASP, 11,12 and this is more frequent in those with dyslipidemia (hypertriglyceridemia and increased LDL), suggestive of ASP resistance. In vivo human studies demonstrate a correlation between increased plasma ASP and delayed postprandial TG clearance in men and women.…”

Lipoprotein lipase deficiency is associated with elevated acylation stimulating protein plasma levels

“…While high plasma ASP is often associated with metabolic disorders (as discussed above), the physiological consequences of chronically elevated ASP levels are still unknown. In vitro studies in adipocytes have shown that ASP stimulates in situ LPL activity by increasing FA uptake and relieving product inhibition (8,11). On the other hand, ASP plays an inhibitory role in skeletal muscle tissue; LPL activity was decreased by 35% in skeletal muscle upon ASP stimulation (11).…”

“…C5L2 is highly expressed in adipose tissue, muscle, and liver (5,7). While insulin directly increases LPL activity in adipocytes (8), ASP stimulates LPL activity indirectly by enhancing cellular uptake and esterification of NEFA, thereby relieving feedback inhibition on LPL (8). Like insulin (9,10), ASP exerts an inhibitory effect on LPL activity in the muscle (11).…”

Relationship Between Obesity and Immune System a Review Article

“…Basal levels of complement activation have rather beneficial metabolic effects, ranging from stimulation of insulin secretion in pancreatic β-cells (ASP, fH) [41,42] to insulin-like actions with regard to adipocyte maturation and energy regulation (adipsin, ASP, C3a, C5a) [43]. In contrast, increased complement action can contribute to metabolic pathology.…”