A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation

Abstract

Liver X receptor (LXR) agonists exert potent antiatherosclerotic actions but simultaneously induce excessive triglyceride (TG) accumulation in the liver. To obtain a detailed insight into the underlying mechanism of hepatic TG accumulation, we used a novel computational modeling approach called analysis of dynamic adaptations in parameter trajectories (ADAPT). We revealed that both input and output fluxes to hepatic TG content are considerably induced on LXR activation and that in the early phase of LXR agonism, hepatic steatosis results from only a minor imbalance between the two. It is generally believed that LXR-induced hepatic steatosis results from increased de novo lipogenesis (DNL). In contrast, ADAPT predicted that the hepatic influx of free fatty acids is the major contributor to hepatic TG accumulation in the early phase of LXR activation. Qualitative validation of this prediction showed a 5-fold increase in the contribution of plasma palmitate to hepatic monounsaturated fatty acids on acute LXR activation, whereas DNL was not yet significantly increased. This study illustrates that complex effects of pharmacological intervention can be translated into distinct patterns of metabolic regulation through state-ofthe-art mathematical modeling.-Hijmans, B. S., Tiemann, C. A., Grefhorst, A., Boesjes, M., van Dijk, T. H., Tietge, U. J. F., Kuipers, F., van Riel, N. A. W., Groen, A. K., Oosterveer, M. H. A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation. FASEB J. 29, 1153-1164 (2015). www.fasebj.org Key Words: computational modeling • T0901317 • fatty liver • FFA flux • VLDL metabolism LIVER X RECEPTORS (LXRS) are transcription factors that play a central role in the regulation of lipid and carbohydrate metabolism (1). Under physiologic conditions, LXRs are activated by oxygenated metabolites of cholesterol (2). Because LXR agonism raises plasma HDL levels (3, 4), potently promotes cholesterol excretion (5, 6), and reduces atherosclerotic plaque formation in rodent models (7), LXR is considered an attractive drug target for antiatherosclerotic therapies (8, 9). LXR agonists, however, also cause severe hepatic triglyceride (TG) accumulation in animal models (3,4). This has been attributed to transcriptional up-regulation of lipogenic genes (10, 11) and subsequent stimulation of de novo lipogenesis (DNL) in the liver. The induction of hepatic steatosis is a major drawback for the clinical application of LXR agonists because this condition may predispose to the development of nonalcoholic steatohepatitis and eventually hepatocarcinoma (12).Increases in hepatic TG synthesis and content on pharmacological LXR activation are generally believed to be driving forces for the secretion of large, TG-rich very lowdensity lipoprotein (VLDL) particles by the liver (4). Published data on the effects of pharmacologic LXR agonism on plasma VLDL-TG levels indicate transient effects in rodents and nonhuman primates (4,11,(13)(14)(15). The mechanistic b...

Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake

“…In support of this procedure is the fact that at the beginning of a high-fat dietary intervention the excess supply of fat does, in fact, inhibit the process of DNL [106]. In accordance, Hijmans et al [70] predicted with a novel computational modelling approach that not increased DNL but the amount of FA influx determines hepatic fat load. Beyond our modelling approach, the comprehensive modelling study by Ashworth et al [48] factors in both carbohydrate and energy metabolism and shed light on the impact of insulin resistance and DNL for a zonated TG accumulation under a high-intake diet.…”

“…Donnelly et al [33] showed already that the plasma FA supply drives mainly the hepatic TG accumulation and that its concentration is increased in NAFLD patients. In support for this, Hijmans et al [70] found by computational modelling that the hepatic influx of FAs is a major contributor to hepatic TG accumulation in early phases. But how the uptake process may shape the establishment of the zonated TG accumulation is unknown.…”

FXR overexpression alters adipose tissue architecture in mice and limits its storage capacity leading to metabolic derangements

“…Yet, exposure to a positive energy balance provokes ectopic lipid accumulation in liver and muscle. As adipose-derived fatty acid flux contributes 60-80% of the hepatic lipid influx in both mice and men, subtle changes in adipose output may lead to severe hepatic consequences over time (70,71). Recently, for instance, adipose tissue lipolysis rates were found to drive hepatic glucose production (47).…”

miR-212-5p suppresses lipid accumulation by targeting FAS and SCD1

“…It is shown that the GCN2/mTOR/S6K1 and AMPK pathways play important roles in regulating hepatic insulin sensitivity by leucine deprivation (Xiao et al 2011); many studies have demonstrated that insulin resistance is accompanied by liver steatosis (Savage et al 2007, Kumashiro et al 2011, Birkenfeld & Shulman 2014, which suggests that GCN2 may be involved in regulating hepatic TG levels. On the other hand, GCN2 may regulate other transcription factors like C/EBPβ and LXRα (Guo & Cavener 2007), which may be involved in regulating fatty liver (Rahman et al 2007, Hijmans et al 2015, Hsieh et al 2016.…”