Involvement of peroxisome proliferator-activated receptors in cardiac and vascular remodeling in a novel minipig model of insulin resistance and atherosclerosis induced by consumption of a high-fat/cholesterol diet

Abstract

BackgroundA long-term high-fat/cholesterol (HFC) diet leads to insulin resistance (IR), which is associated with inflammation, atherosclerosis (AS), cardiac sympathovagal imbalance, and cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) and nuclear factor ĸB (NF-κB) are involved in the development of IR-AS. Thus, we elucidated the pathological molecular mechanism of IR-AS by feeding an HFC diet to Tibetan minipigs to induce IR and AS.MethodsMale Tibetan minipigs were fed either a normal diet or an HFC diet for 24 weeks. Thereafter, the minipigs were tested for physiological and biochemical blood indices, blood pressure, cardiac function, glucose tolerance, heart rate variability (HRV), and PPAR-associated gene and protein expression levels.ResultsHFC-fed minipigs exhibited IR through increased body weight, fasting blood glucose levels, plasma cholesterol and its composition, and insulin and free fatty acid (FFA) levels; decreased insulin sensitivity; impaired glucose tolerance; and hypertension. Increased C-reactive protein (CRP) levels, cardiac dysfunction, depressed HRV, and the up-regulation of PPAR expression in the abdominal aorta concomitant with down-regulation in the heart tissue were observed in HFC-fed minipigs. Furthermore, the levels of NF-κBp65, IL-1β, TNF-α, MCP-1, VCAM-1, ICAM-1, MMP-9, and CRP proteins were also significantly increased.ConclusionsThese data suggest that HFC-fed Tibetan minipigs develop IR and AS and that PPARs are involved in cardiovascular remodeling and impaired function.

Bioinformatics analysis of vascular RNA-seq data revealed hub genes and pathways in a novel Tibetan minipig atherosclerosis model induced by a high fat/cholesterol diet

“…After 4 weeks of environmental accommodation, the animals were divided into a normal control (NC) group and an atherosclerosis model group with 5 animals per group. The atherosclerosis model was established by feeding minipigs with a high-fat/cholesterol (HFC) diet (containing 15% shortening oil, 1.5% cholesterol, 10% egg yolk powder, and 73.5% basal feed) for 24 weeks, as we previously described [9]. Minipigs were euthanized at the 24th week.…”

“…Furthermore, the omnivorous nature of pigs makes them highly suitable for studying dietarybased patterns and for translating findings from pigs to humans [5]. In particular, Tibetan minipigs have many advantages as a model for studying diet-related cardiovascular metabolic diseases [9,10]. Our previous studies have shown that Tibetan minipigs are a viable model for studying atherosclerosis induced by dietary patterns.…”

“…Our previous studies have shown that Tibetan minipigs are a viable model for studying atherosclerosis induced by dietary patterns. They can form atherosclerosis with 24 weeks of a highfat/cholesterol diet, and have characteristics like lipid disorders, insulin resistance, hypertension and cardiac dysfunction [9]. The lipid metabolism changes and atherosclerotic lesions in the Tibetan minipig model are also very close to those in humans, but the underlying molecular pathological mechanisms are not yet clear.…”

Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet

“…Furthermore, peripheral fat accumulation is associated with macrophage infiltration into adipose tissue, which promotes the release of proinflammatory cytokines including tumour necrosis factor alpha (TNFα) (Wellen and Hotamisligil 2005). In a recent study, significantly higher levels of inflammatory markers, including TNFα, were found in the cardiac tissue of Tibetan mini pigs as a result of being fed a HF diet for 24 weeks (Yongming, Zhaowei et al 2015). Furthermore, rats fed a HF diet for 10 weeks demonstrated increased TNFα levels in the cortex of their kidneys (Elmarakby and Imig 2010).…”

Intrauterine programming of lipid metabolic alterations in the heart of the offspring of diabetic rats is prevented by maternal diets enriched in olive oil

“…Impaired lipid metabolism and the ectopic deposition of fat have been found involved in the long‐term programming of diseases and related to the generation of a proinflammatory environment . Peroxisome proliferator activated receptor α (PPARα) is a ligand‐activated transcription factor with key functions in the regulation of lipid metabolism, antioxidant and antiinflammatory pathways, highly relevant in cardiac energy metabolism, cardiovascular remodeling, and vascular homeostasis . PPARα is one of the three identified PPARs, nuclear receptors that are activated by endogenous ligands of lipid nature, including diverse unsaturated fatty acids .…”