Triglyceride-rich lipoproteins and insulin resistance in patients with chronic hepatitis C receiving direct-acting antivirals

Hepatitis C virus (HCV), a highly prevalent RNA-virus, causes acute and chronic liver damage leading to cirrhosis and hepatocellular carcinoma [1]. Therapies based on the use of direct-acting antivirals (DAAs) are widely available and highly effective in the eradication of HCV, with sustained virological responses over 95% [2]. There is growing evidence that DAA therapies may have a positive effect on metabolic health. However, the mechanisms by which these beneficial changes in metabolic homeostasis occur are not yet clear [3].

In addition to hepatic alterations, HCV can also produce a variety of extrahepatic manifestations [4]⁠. Multiple steps of the HCV replication cycle are closely linked to host lipid metabolism. In particular, HCV associates with lipoproteins to be shipped out from the liver as highly infective lipo-viro particles (LVPs) [5]. These particles are critical for the infectivity of the HCV as they could provide protection against antibody-mediated neutralization. LPV were described as triglyceride-rich very low-density lipoproteins (VLDL) [6], including apolipoproteins B(APOB) and E (APOE) [[6], [7], [8], [9]]. Coincidently, low VLDL- and LDL-cholesterol levels are characteristic of chronic HCV infection [10]⁠. Despite the apparently beneficial cholesterol reduction, this lipid profile is associated with increased risk of steatosis [11], type 2 diabetes (T2D) [12], and cardiovascular disease (CVD) (reviewed in Refs. [13,14]). These counter-intuitive phenomena may be explained, at least partially, by lipid disturbances caused by HCV infection, which markedly interfere with the host metabolic homeostasis, ultimately causing hypolipidemia and insulin resistance (IR).

Mounting evidence indicates that abnormalities in triglyceride-rich lipoproteins, such as VLDL, are associated with IR [15,16]. This interdependence of glycemic and lipid modulation has been recently described in patients with chronic HCV infection receiving DAA treatment [17,18]. Recently, a nuclear magnetic resonance (NMR) spectroscopy-based method was developed to quantify different types of lipoparticles and measure their size, shape, and composition [19]. This new tool opens a new scenario for the study of the structure and function of lipoproteins. Using ultracentrifugation technology, changes in different lipoprotein subclasses in chronic carriers of HCV undergoing DAA therapy [20], as well as in patients co-infected with HIV/HCV, have been described [21]. However, the association of particle subfraction number and content with IR, estimated as homeostasis model assessment (HOMA) has not been determined in a population-based cohort so far. Therefore, we hypothesize that further evaluation of the lipoparticle characteristics of HCV-infected patients and their trajectories during the post-substained virological response (SVR) phase may shed light on the mechanism by which changes in IR occur. Accordingly, the aims of this study were 1) to characterize dyslipidemia in naive HCV-infected individuals with the application of the NMR method to calculate lipoprotein content, number, and size and 2) to evaluate the association of metabolic changes and NMR-profiled lipoparticules after virus eradication with DAA therapy, before and after treatment, and 1 year post-treatment.

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