Circulating Interlukin-32 and Altered Blood Pressure Control in Individuals with Metabolic Dysfunction

Abstract

Fatty liver disease is most frequently related to metabolic dysfunction (MAFLD) and associated comorbidities, heightening the risk of cardiovascular disease, and is associated with higher hepatic production of IL32, a cytokine linked with lipotoxicity and endothelial activation. The aim of this study was to examine the relationship between circulating IL32 concentration and blood pressure control in individuals with metabolic dysfunction at high risk of MAFLD. IL32 plasma levels were measured by ELISA in 948 individuals with metabolic dysfunction enrolled in the Liver-Bible-2021 cohort. Higher circulating IL32 levels were independently associated with systolic blood pressure (estimate +0.008 log10 per 1 mmHg increase, 95% c.i. 0.002–0.015; p = 0.016), and inversely correlated with antihypertensive medications (estimate −0.189, 95% c.i. −0.291–−0.088, p = 0.0002). Through multivariable analysis, IL32 levels predicted both systolic blood pressure (estimate 0.746, 95% c.i 0.173–1.318; p = 0.010) and impaired blood pressure control (OR 1.22, 95% c.i. 1.09–1.38; p = 0.0009) independently of demographic and metabolic confounders and of treatment. This study reveals that circulating IL32 levels are associated with impaired blood pressure control in individuals at risk of cardiovascular disease.

Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women

“…The Liver-Bible-2022 cohort included 1,142 individuals with metabolic dysfunction 60 – 62 , who were consecutively enrolled from July 2019 to July 2022, and for whom information on genomic data was available. These were apparently healthy blood donors, aged 40–65 years, who were selected for a comprehensive liver disease, metabolic and cardiovascular screening, owing to the presence of at least three metabolic risk abnormalities, from overweight/obesity (defined as BMI ≥ 25 kg m −2 ), hypertension (blood pressure ≥130/85 mmHg or antihypertensive treatment), dysglycemia (fasting glucose level ≥100 mg dl −1 or use of glucose-lowering agents), low plasma high-density lipoprotein (HDL)-cholesterol (<45 mg dl −1 in men and <55 mg dl −1 in women) or high plasma triglycerides (≥150 mg dl −1 or lipid-lowering treatment).…”

IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids

“…Also, we examined the impact of rs76580947 minor allele on IL-32 circulating levels in a total of 955 Italian individuals with dysmetabolism from the Liver-BIBLE 2020 cohort. 10 , 33 The clinical features of Liver-BIBLE 2020 cohort stratified according to rs76580947 genotype are shown in Table S2 . The frequency of IL32 rs76580947 G>C minor allele was 0.119 in agreement with gnomAD database, and the genotype distribution conformed to Hardy-Weinberg equilibrium (p = 0.28).…”

“… 62 Lastly, the effect of the IL32 genetic variant on circulating IL32 levels was validated in the Liver-BIBLE cohort 2020 comprising of 955 healthy individuals with dysmetabolism presented for blood donation from June 2019 to February 2021 at the Transfusion Medicine and Hematology unit of Fondazione Ca’ Granda Hospital (Liver-Bible cohort 2020). 10 , 33 Briefly, inclusion criteria were age 40–65, associated with at least three of the following features: overweight or obesity (Body mass index (BMI) > 25 kg/m 2 ), increased fasting glucose or type 2 diabetes (fasting glucose≥100 mg/dl), triglycerides≥150 mg/dl, HDL<45/55 in M/F, arterial hypertension. Individuals with chronic degenerative disorders, except for well controlled arterial hypertension, compensated hypothyroidism, and type 2 diabetes not requiring pharmacological therapy, were excluded from the cohort at first evaluation.…”

“…By examining the differential hepatic gene expression of morbidly obese individuals, we and others identified interleukin 32 (IL-32) as a highly upregulated transcript in those with severe liver damage, namely metabolic dysfunction-associated steatohepatitis (MASH) significant liver fibrosis and arterial hypertension. 8 , 9 , 10 We then demonstrated the potential of this protein as a novel circulating biomarker for detecting severe SLD non-invasively. 8 Serendipitously, transcriptomic analyses of liver from a cohort of individuals at risk for SLD showed that IL-32 was associated with SLD progression.…”

Non‐alcoholic fatty liver disease mediates the effect of obesity on arterial hypertension

“…For example, the renin‐angiotensin‐aldosterone system controls not only many aspects of CV pathophysiology 38 but also liver‐related outcomes 39–43 . Many adipokines and gastrointestinal hormones, 44 inflammatory molecules and mediators of atherosclerosis that are produced in the liver, 17 CNS pathways that influence food intake and energy expenditure, 45 and cytokines linked with lipotoxicity and endothelial activation such as IL32 46,47 …”