Changes in plasma lipids predict pravastatin efficacy in secondary prevention

Jayawardana, Kaushala S.; Mundra, Piyushkumar A.; Giles, Corey; Barlow, Christopher K.; Nestel, Paul J.; Barnes, Elizabeth H; Kirby, Adrienne; Thompson, Peter L.; Sullivan, David; Alshehry, Zahir H.; Mellett, Natalie A.; Huynh, Kevin; McConville, Malcolm J.; Zoungas, Sophia; Hillis, Graham S.; Chalmers, John; Woodward, Mark; Marschner, Ian C.; Wong, Gerard; Kingwell, Bronwyn A.; Simes, John; Tonkin, Andrew; Meikle, Peter J.

doi:10.1172/jci.insight.128438

Cited by 14 publications

(15 citation statements)

References 26 publications

(30 reference statements)

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“…This was reflected in the lipidome as lipid species were altered in response to simvastatin treatment. Simvastatin significantly decreased the PI(36:2)/PC(18:0_20:4) lipid ratio in Hep3B cells, consistent with the findings of Jayawardana et al [12]. Specifically, the majority of PI species decreased whilst the PC(18:0_20:4) constituent of the lipid ratio increased in both studies.…”

Section: Discussionsupporting

confidence: 91%

“…This study aimed to better understand the mechanisms by which statins modulate the PI(36:2)/PC(18:0_20:4) lipid ratio. To achieve this, we developed a cell-based model that reflected the statin-induced changes observed in the human plasma lipidome by Jayawardana et al [12]. Hep3B cells were selected as the majority of lipids are predominantly synthesised within hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Hep3B cells were selected as the majority of lipids are predominantly synthesised within hepatocytes. Criteria to confirm the biological relevance of the model included a significant decrease in the lipid ratio PI(36:2)/PC(18:0_20:4), as well as free cholesterol and cholesterol esters (CE), indicating successful inhibition of cholesterol synthesis and validation of the key findings from Jayawardana et al [12]. Changes in phosphatidylinositol (PI) species and species containing arachidonic acid (AA; 20:4) were also considered.…”

Section: Resultsmentioning

confidence: 99%

“…Changes in phosphatidylinositol (PI) species and species containing arachidonic acid (AA; 20:4) were also considered. Simvastatin was utilised as it induces lipid metabolic changes that are most reflective of those observed in the human trial [12]. Furthermore, as simvastatin is a second generation statin, it has a significantly improved efficacy in reducing LDL-C levels compared to the earlier statins, including pravastatin [13].…”

Section: Resultsmentioning

confidence: 99%

“…In one of the largest lipidomic studies to date, Jayawardana and colleagues characterised changes in the plasma lipidome in response to pravastatin treatment to define the relationship between statin treatment, plasma lipids and risk reduction of future cardiovascular events in secondary prevention [12]. The authors reported that while the modulation of LDL-C levels accounted for 32% of the observed risk reduction for secondary coronary events, the ratio of two lipid species, phosphatidylinositol (PI(36:2)) and phosphatidylcholine (PC(18:0_20:4)) accounted for 58% of the risk reduction, thus accounting for the majority of the treatment effect of pravastatin in risk reduction.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Simvastatin on Lipidomic Markers of Cardiovascular Risk in Human Liver Cells Is Secondary to the Modulation of Intracellular Cholesterol

et al. 2021

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Statins are the first-line lipid-lowering therapy for reducing cardiovascular disease (CVD) risk. A plasma lipid ratio of two phospholipids, PI(36:2) and PC(18:0_20:4), was previously identified to explain 58% of the relative CVD risk reduction associated with pravastatin, independent of a change in low-density lipoprotein-cholesterol. This ratio may be a potential biomarker for the treatment effect of statins; however, the underlying mechanisms linking this ratio to CVD risk remain unclear. In this study, we investigated the effect of altered cholesterol conditions on the lipidome of cultured human liver cells (Hep3B). Hep3B cells were treated with simvastatin (5 μM), cyclodextrin (20 mg/mL) or cholesterol-loaded cyclodextrin (20 mg/mL) for 48 hours and their lipidomes were examined. Induction of a low-cholesterol environment via simvastatin or cyclodextrin was associated with elevated levels of lipids containing arachidonic acid and decreases in phosphatidylinositol species and the PI(36:2)/PC(18:0_20:4) ratio. Conversely, increasing cholesterol levels via cholesterol-loaded cyclodextrin resulted in reciprocal regulation of these lipid parameters. Expression of genes involved in cholesterol and fatty acid synthesis supported the lipidomics data. These findings demonstrate that the PI(36:2)/PC(18:0_20:4) ratio responds to changes in intracellular cholesterol abundance per se, likely through a flux of the n-6 fatty acid pathway and altered phosphatidylinositol synthesis. These findings support this ratio as a potential marker for CVD risk reduction and may be useful in monitoring treatment response.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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