Role of PAI-1 in hepatic steatosis and dyslipidemia

Levine, Joshua A.; Oleaga, Carlota; Eren, Mesut; Amaral, Ansel P.; Meng, Shu; Lux, Elizabeth; Khan, Sadiya S.; Shah, Sanjiv J.; Omura, Yasuhiro; Pamir, Nathalie; Hay, Joshua; Barish, Grant D.; Miyata, Toshio; Tavori, Hagai; Fazio, Sergio; Vaughan, Douglas E.

doi:10.1038/s41598-020-79948-x

Cited by 65 publications

(50 citation statements)

References 41 publications

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“…Disruption of PCSK9-LDLR interaction is still compatible with downstream signaling effects, as the antibody-antigen complex may still clear the circulation and enter the liver via LDLR-independent target-mediated mechanisms. For example, we have shown that plasma PAI-1 levels decrease following PCSK9 blockade, an effect that most probably is independent of LDLR ( 47 ). However, no metabolic effects of the increased plasma PCSK9 levels induced by PCSK9i therapy have been thus far identified, although we can speculate that situations leading to dissociation of the antigen from the therapeutic antibody would likely trigger an increase in cholesterol levels.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies

Oleaga

Shapiro

Hay

et al. 2021

Journal of the American College of Cardiology

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BACKGROUND Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold. OBJECTIVES The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis. METHODS In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i. RESULTS In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion. CONCLUSIONS PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects.

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Section: Discussionmentioning

confidence: 99%

Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies

Oleaga

Shapiro

Hay

et al. 2021

Journal of the American College of Cardiology

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“…Using cultured adipocytes from PAI-1+/+ and PAI-1-/mice, the deletion of PAI-1 in adipocytes ameliorated insulin resistance by promoting glucose uptake and adipocyte differentiation [36]. Inhibition of plasma PAI-1 activity also resulted in improved hyperlipidemia in a diet-induced obese mouse model [37]. In mouse models, pharmacological inhibition of PAI-1 prevented hepatic steatosis and reduced serum cholesterol level by reducing PCSK9 synthesis [37].…”

Section: Experimental Studiesmentioning

confidence: 99%

The Roles and Associated Mechanisms of Adipokines in Development of Metabolic Syndrome

Kim

et al. 2022

Molecules

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Metabolic syndrome is a cluster of metabolic indicators that increase the risk of diabetes and cardiovascular diseases. Visceral obesity and factors derived from altered adipose tissue, adipokines, play critical roles in the development of metabolic syndrome. Although the adipokines leptin and adiponectin improve insulin sensitivity, others contribute to the development of glucose intolerance, including visfatin, fetuin-A, resistin, and plasminogen activator inhibitor-1 (PAI-1). Leptin and adiponectin increase fatty acid oxidation, prevent foam cell formation, and improve lipid metabolism, while visfatin, fetuin-A, PAI-1, and resistin have pro-atherogenic properties. In this review, we briefly summarize the role of various adipokines in the development of metabolic syndrome, focusing on glucose homeostasis and lipid metabolism.

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“…Finally, changes in these non-traditional biomarkers may be not only due to improvement in weight loss, physical fitness, and physical activity, but also due to changes in traditional risk factors. This finding is not surprising given these factors have also been associated with hypertension ( 49 ), dyslipidemia ( 50 ), and diabetes ( 51 , 52 ). Despite these study limitations, we believe our study provides important information on how an exercise program administered in a real-world setting can improve non-traditional markers of cardiovascular risk.…”

Section: Limitationsmentioning

confidence: 88%

Modest Gains After an 8-Week Exercise Program Correlate With Reductions in Non-traditional Markers of Cardiovascular Risk

Liang

Huang

Hirsch³

et al. 2021

Front. Cardiovasc. Med.

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Background: Although engaging in physical exercise has been shown to reduce the incidence of cardiovascular events, the molecular mechanisms by which exercise mediates these benefits remain unclear. Based on epidemiological evidence, reductions in traditional risk factors only accounts for 50% of the protective effects of exercise, leaving the remaining mechanisms unexplained. The objective of this study was to determine whether engaging in a regular exercise program in a real world clinical setting mediates cardiovascular protection via modulation of non-traditional risk factors, such as those involved in coagulation, inflammation and metabolic regulation.Methods and Results: We performed a prospective, cohort study in 52 sedentary patients with cardiovascular disease or cardiovascular risk factors at two tertiary medical centers between January 1, 2016 and December 31, 2019. Prior to and at the completion of an 8-week exercise program, we collected information on traditional cardiovascular risk factors, exercise capacity, and physical activity and performed plasma analysis to measure levels of fibrinolytic, inflammatory and metabolic biomarkers to assess changes in non-traditional cardiovascular risk factors. The median weight change, improvement in physical fitness, and change in physical activity for the entire cohort were: −4.6 pounds (IQR: +2 pounds, −11.8 pounds), 0.37 METs (IQR: −0.076 METs, 1.06 METs), and 252.7 kcals/week (IQR: −119, 921.2 kcals/week). In addition to improvement in blood pressure and cholesterol, patients who lost at least 5 pounds, expended at least 1,000 additional kcals/week, and/or achieved ≥0.5 MET increase in fitness had a significant reduction in plasminogen activator inhibitor-1 [9.07 ng/mL (95% CI: 2.78–15.35 ng/mL); P = 0.026], platelet derived growth factor beta [376.077 pg/mL (95% CI: 44.69–707.46 pg/mL); P = 0.026); and angiopoietin-1 [(1104.11 pg/mL (95% CI: 2.92–2205.30 pg/mL); P = 0.049)].Conclusion: Modest improvements in physical fitness, physical activity, and/or weight loss through a short-term exercise program was associated with decreased plasma levels of plasminogen activator inhibitor, platelet derived growth factor beta, and angiopoietin, which have been associated with impaired fibrinolysis and inflammation.

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Role of PAI-1 in hepatic steatosis and dyslipidemia

Cited by 65 publications

References 41 publications

Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies

Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies

The Roles and Associated Mechanisms of Adipokines in Development of Metabolic Syndrome

Modest Gains After an 8-Week Exercise Program Correlate With Reductions in Non-traditional Markers of Cardiovascular Risk

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