Prediabetes Induced by Fructose-Enriched Diet Influences Cardiac Lipidome and Proteome and Leads to Deterioration of Cardiac Function prior to the Development of Excessive Oxidative Stress and Cell Damage

Abstract

Prediabetes is a condition affecting more than 35% of the population. In some forms, excessive carbohydrate intake (primarily refined sugar) plays a prominent role. Prediabetes is a symptomless, mostly unrecognized disease which increases cardiovascular risk. In our work, we examined the effect of a fructose-enriched diet on cardiac function and lipidome as well as proteome of cardiac muscle. Male Wistar rats were divided into two groups. The control group received a normal diet while the fructose-fed group received 60% fructose-supplemented chow for 24 weeks. Fasting blood glucose measurement and oral glucose tolerance test (OGTT) showed slightly but significantly elevated values due to fructose feeding indicating development of a prediabetic condition. Both echocardiography and isolated working heart perfusion performed at the end of the feeding protocol demonstrated diastolic cardiac dysfunction in the fructose-fed group. Mass spectrometry-based, high-performance lipidomic and proteomic analyses were executed from cardiac tissue. The lipidomic analysis revealed complex rearrangement of the whole lipidome with special emphasis on defects in cardiolipin remodeling. The proteomic analysis showed significant changes in 75 cardiac proteins due to fructose feeding including mitochondria-, apoptosis-, and oxidative stress-related proteins. Nevertheless, just very weak or no signs of apoptosis induction and oxidative stress were detected in the hearts of fructose-fed rats. Our results suggest that fructose feeding induces marked alterations in the cardiac lipidome, especially in cardiolipin remodeling, which leads to mitochondrial dysfunction and impaired cardiac function. However, at the same time, several adaptive responses are induced at the proteome level in order to maintain a homeostatic balance. These findings demonstrate that even very early stages of prediabetes can impair cardiac function and can result in significant changes in the lipidome and proteome of the heart prior to the development of excessive oxidative stress and cell damage.

Elevated myocardial fructose and sorbitol levels are associated with diastolic dysfunction in diabetic patients, and cardiomyocyte lipid inclusions in vitro

“…Population studies have associated diabetes and cardiovascular disease with escalating fructose consumption, but whether fructose plays a direct role remains controversial 2 , 3 . Experimentally, a high fructose diet induces cardiomyocyte metabolic and functional disturbances 4 – 7 . Although reported values of circulating fructose levels vary widely (5 µM–1.9 mM 8 , 9 ), evidence suggests that plasma fructose is elevated in diabetic patients 10 .…”

Exogenous exposure to dihydroxyacetone mimics high fructose induced oxidative stress and mitochondrial dysfunction

“…High‐dose fructose also elevated oxidative stress in response to increased 8‐OHdG levels in Sprague–Dawley rats (Cioffi et al ., 2017). Wistar rats exposed to a 60% fructose dose for 24 weeks showed elevated methylglyoxal and increased oxidative stress (Szucs et al ., 2019). Of note, 60% fructose also elevated oxidative stress in Spontaneously Hypertensive rats, Wistar rats, and C57BL/6 mice (Cavarape et al ., 2001; Mellor et al ., 2010; Wu et al ., 2017).…”

“…However, hepatic tissue from Wistar rats with 25% fructose administration exhibited no elevation in ROS levels (Garcia‐Berumen et al ., 2019; Yamada et al ., 2019). Cardiac tissue showed increased ROS for C57BL/6 mice with 10% and 60% dietary fructose and Wistar rats given 60% fructose (Zhang et al ., 2015; Szucs et al ., 2019). Only limited analysis of kidney tissue was conducted with ROS formation observed after 20% fructose exposure in Fischer rat models (Dornas et al ., 2017).…”

“…C57BL/6 mice administered a 60% fructose dose experienced a non‐significant increase of thioredoxin‐2 ( Thx2 ) gene expression levels (Mellor et al ., 2010). Wistar rats administered 60% fructose had elevated expression of the elongation of very‐long‐chain fatty acids protein 6 ( Elovl6 ) enzyme, which has an important role in NAFLD by transforming C16 saturated and monounsaturated fatty acids into C18 compounds (Szucs et al ., 2019).…”

“…High fructose exposed Wistar rats had decreased catalase mRNA expression in the liver, heart, skeletal muscle, and adipose tissue, which is pro‐apoptotic (Cavarape et al ., 2001). There were also increased levels of creatine kinase (CK), CK‐MB, and lactate dehydrogenase (LDH), which are indicative of myocardial injury (Szucs et al ., 2019). However, a separate Wistar rat study found no change in caspase‐7 and Bax expression upon treatment; however, there was an increase in anti‐apoptotic 3‐ketoacyl‐CoA thiolase in mitochondria of cardiac tissue, which diminished Bnip3‐induced apoptosis (Szucs et al ., 2019).…”