Investigation of human apoB48 metabolism using a new, integrated non‐steady‐state model of apoB48 and apoB100 kinetics

Abstract

BackgroundTriglyceride‐rich lipoproteins and their remnants have emerged as major risk factors for cardiovascular disease. New experimental approaches are required that permit simultaneous investigation of the dynamics of chylomicrons (CM) and apoB48 metabolism and of apoB100 in very low‐density lipoproteins (VLDL).MethodsMass spectrometric techniques were used to determine the masses and tracer enrichments of apoB48 in the CM, VLDL 1 and VLDL 2 density intervals. An integrated non‐steady‐state multicompartmental model was constructed to describe the metabolism of apoB48‐ and apoB100‐containing lipoproteins following a fat‐rich meal, as well as during prolonged fasting.ResultsThe kinetic model described the metabolism of apoB48 in CM, VLDL 1 and VLDL 2. It predicted a low level of basal apoB48 secretion and, during fat absorption, an increment in apoB48 release into not only CM but also directly into VLDL 1 and VLDL 2. ApoB48 particles with a long residence time were present in VLDL, and in subjects with high plasma triglycerides, these lipoproteins contributed to apoB48 measured during fasting conditions. Basal apoB48 secretion was about 50 mg day−1, and the increment during absorption was about 230 mg day−1. The fractional catabolic rates for apoB48 in VLDL 1 and VLDL 2 were substantially lower than for apoB48 in CM.DiscussionThis novel non‐steady‐state model integrates the metabolic properties of both apoB100 and apoB48 and the kinetics of triglyceride. The model is physiologically relevant and provides insight not only into apoB48 release in the basal and postabsorptive states but also into the contribution of the intestine to VLDL pool size and kinetics.

Subclinical Arteriosclerosis is Associated with Common Vascular Risk Factors in Long-Term Survivors of Testicular Cancer

“…Data from binary regression analyses did not find any association between cases and SA; however, SA was associated independently with major CV risk factors such as age, smoking, hypertension, ApoB, and HDL cholesterol, as expected. Fasting and postprandial apolipoprotein B48, the main protein in chylomicrons, and its remnants [38] have been associated with SA in many studies in populations both with diabetes [39,40] and without [41,42]. However, apolipoprotein B48 was not associated with SA in our study, even when we removed ApoB from the equation.…”

The dual glucose‐dependent insulinotropic peptide and glucagon‐like peptide‐1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes

“…The lack of correlation between changes in preheparin LPL mass and changes in triglycerides could also suggest a role of other determinants of triglyceride concentrations, such as apoC‐III. Indeed, triglyceride clearance rates in both the fasting and postprandial states have been shown to be closely linked to plasma apoC‐III levels, but not related to postheparin plasma LPL activity 35,36 . The reduction of apoC‐III levels with tirzepatide is unlikely to be explained by direct GIP receptor agonism in hepatocytes because GIP receptors do not appear to be expressed in the liver 37,38 .…”

“…22,23 Notably, GIP enhances the vaso- LPL activity. 35,36 The reduction of apoC-III levels with tirzepatide is unlikely to be explained by direct GIP receptor agonism in hepatocytes because GIP receptors do not appear to be expressed in the liver. 37,38 A direct effect of tirzepatide on intestinal GIP receptors could theoretically reduce intestinal apoC-III production, but this also seems unlikely to explain reduced fasting apoC-III levels.…”

“…This is not unexpected, as apoC-III is critical for triglyceride metabolism, through inhibition of LPL activity and impairment of triglyceride-rich lipoprotein clearance by promoting the uptake of TFL remnants by the liver. 8,36 Weight loss with bariatric surgery is consistently accompanied not only by HbA1c reduction, but has also resulted in markedly reduced plasma triglycerides and apoC-III, and this decrease was accompanied by a redistribution of apoC-III from triglyceride-rich lipoproteins to HDL. 39 However, although tirzepatide resulted in better glucose control and greater weight loss than dulaglutide, the multiple linear regression analysis indicated that tirzepatide-induced weight loss only explained a small portion of the variability in triglycerides.…”

Effects of gastric bypass surgery on postprandial gut and systemic lipid handling

“…Assessment of fat absorption and utilization represents a yet unsolved challenge, since dietary fat is secreted as chylomicrons in the lymph and chlyomicrons-TG are very quickly cleared from the circulation [15]. Furthermore, current methods for isolation of chylomicrons relying on ultracentrifugation are known have low specificity, since the Sf > 400 and Sf 20e400 fractions may both contain chylomicrons as indicated by the presence of apoB48 [16]. Monitoring of plasma apoB48 concentrations can provide valuable insights into chylomicrons metabolism since this apolipoprotein is synthesized in enterocytes and secreted together with TG as chylomicrons in gut lacteals to be released in the systemic circulation, thus escaping first pass hepatic metabolism.…”