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Apolipoprotein A5 reduces clearance of VLDL by altering apolipoprotein E content

Journal Article · · Journal of Lipid Research
 [1];  [2];  [1];  [3];  [4];  [5];  [2];  [1];  [1]
  1. Univ. of Cincinnati, OH (United States)
  2. Cincinnati Children’s Hospital Medical Center, OH (United States); Univ. of Cincinnati, OH (United States)
  3. Univ. of Washington, Seattle, WA (United States)
  4. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
  5. Univ. of Cincinnati, OH (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
+ Show Author Affiliations

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of very low-density lipoprotein (VLDL) particles in vivo. One way APOA5 exerts its effects is through modulation of lipoprotein lipase (LPL) activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 knockout (KO) and wild-type (WT) mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 K mice was cleared significantly more slowly by cultured hepatocytes. Proteomics experiments from two independent laboratories identified consistent depletion of 17 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including APOE and serum amyloid A1 (SAA1). Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response.

Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH)
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
3001879
Report Number(s):
PNNL-SA--213215
Journal Information:
Journal of Lipid Research, Journal Name: Journal of Lipid Research Journal Issue: 11 Vol. 66; ISSN 0022-2275
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

LPL
MS
VLDL
apolipoprotein
apolipoprotein A-V
apolipoprotein E
lipolysis
structure
triglyceride-rich