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

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.