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Changes in Apolipoprotein A1-Associated Proteomic Composition After Pioglitazone Treatment Versus Weight Loss

Parsa, Shyon ; Collier, Timothy S. ; McPhaul, Michael J. ; Melander, Olle LU orcid ; Knowles, Joshua W. ; Rohatgi, Anand and Abbasi, Fahim (2025) In International Journal of Molecular Sciences 26(21).
Abstract

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108):... (More)

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO n = 38 or weight loss, WL n = 70). Paired t-tests assessed pre- and post-intervention changes. At baseline, several ApoA1-associated proteins significantly correlated with SSPG. Both interventions improved IR (p < 0.01). PIO led to significant increases in 14 ApoA1-associated proteins, including ApoC1–C4, ApoA2, ApoA4, ApoD, ApoE, LCAT, and PON1/3. WL increased several ApoA1-associated proteins, including ApoA4, ApoD, ApoM, and PON1/3. In conclusion, IR is associated with a pro-atherogenic ApoA1 proteome, and both interventions improve this profile. However, PIO has a broader proteomic impact. These findings highlight the potential of targeting the ApoA1 proteome to reduce residual ASCVD risk.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
apolipoprotein A1, atherogenic dyslipidemia, insulin resistance, pioglitazone, proteomics
in
International Journal of Molecular Sciences
volume
26
issue
21
article number
10690
publisher
MDPI AG
external identifiers
  • scopus:105021598218
  • pmid:41226726
ISSN
1661-6596
DOI
10.3390/ijms262110690
language
English
LU publication?
yes
id
b9f99c92-f855-49dc-acfa-91f871a788f9
date added to LUP
2026-01-30 15:22:17
date last changed
2026-01-31 03:06:13
@article{b9f99c92-f855-49dc-acfa-91f871a788f9,
  abstract     = {{<p>Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO n = 38 or weight loss, WL n = 70). Paired t-tests assessed pre- and post-intervention changes. At baseline, several ApoA1-associated proteins significantly correlated with SSPG. Both interventions improved IR (p &lt; 0.01). PIO led to significant increases in 14 ApoA1-associated proteins, including ApoC1–C4, ApoA2, ApoA4, ApoD, ApoE, LCAT, and PON1/3. WL increased several ApoA1-associated proteins, including ApoA4, ApoD, ApoM, and PON1/3. In conclusion, IR is associated with a pro-atherogenic ApoA1 proteome, and both interventions improve this profile. However, PIO has a broader proteomic impact. These findings highlight the potential of targeting the ApoA1 proteome to reduce residual ASCVD risk.</p>}},
  author       = {{Parsa, Shyon and Collier, Timothy S. and McPhaul, Michael J. and Melander, Olle and Knowles, Joshua W. and Rohatgi, Anand and Abbasi, Fahim}},
  issn         = {{1661-6596}},
  keywords     = {{apolipoprotein A1; atherogenic dyslipidemia; insulin resistance; pioglitazone; proteomics}},
  language     = {{eng}},
  number       = {{21}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Changes in Apolipoprotein A1-Associated Proteomic Composition After Pioglitazone Treatment Versus Weight Loss}},
  url          = {{http://dx.doi.org/10.3390/ijms262110690}},
  doi          = {{10.3390/ijms262110690}},
  volume       = {{26}},
  year         = {{2025}},
}