Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Abstract

Human studies support a strong association between hypertriglyceridemia and atherosclerotic cardiovascular disease (CVD). However, whether a causal relationship exists between hypertriglyceridemia and increased CVD risk is still unclear. One plausible explanation for the difficulty establishing a clear causal role for hypertriglyceridemia in CVD risk is that lipolysis products of triglyceride-rich lipoproteins (TRLs), rather than the TRLs themselves, are the likely mediators of increased CVD risk. This hypothesis is supported by studies of rare mutations in humans resulting in impaired clearance of such lipolysis products (remnant lipoprotein particles; RLPs). Several animal models of hypertriglyceridemia support this hypothesis and have provided additional mechanistic understanding. Mice deficient in lipoprotein lipase (LPL), the major vascular enzyme responsible for TRL lipolysis and generation of RLPs, or its endothelial anchor GPIHBP1, are severely hypertriglyceridemic but develop only minimal atherosclerosis as compared with animal models deficient in apolipoprotein (APO) E, which is required to clear TRLs and RLPs. Likewise, animal models convincingly show that increased clearance of TRLs and RLPs by LPL activation (achieved by inhibition of APOC3, ANGPTL3, or ANGPTL4 action, or increased APOA5) results in protection from atherosclerosis. Mechanistic studies suggest that RLPs are more atherogenic than large TRLs because they more readily enter the artery wall, and because they are enriched in cholesterol relative to triglycerides, which promotes pro-atherogenic effects in lesional cells. Other mechanistic studies show that hepatic receptors (LDLR and LRP1) and APOE are critical for RLP clearance. Thus, studies in animal models have provided additional mechanistic insight and generally agree with the hypothesis that RLPs derived from TRLs are highly atherogenic whereas hypertriglyceridemia due to accumulation of very large TRLs in plasma is not markedly atherogenic in the absence of TRL lipolysis products.

Carrot Juice Consumption Reduces High Fructose-Induced Adiposity in Rats and Body Weight and BMI in Type 2 Diabetic Subjects

“…23 However, the expression data of these pathway proteins in the liver, such as GPAT1 (lipogenesis), MTTP (lipoprotein secretion) and PT1 (fatty acid β-oxidation), and the plasma β-hydroxy butyrate levels suggest the role of lipoprotein lipase (LPL)-mediated extrahepatic tissue clearance of plasma triglyceride in regulating hypertriglyceridemia, as the lipoprotein lipase (LPL) present in the vascular bed of adipose tissue and muscle involves in the uptake of triglyceride from the triglyceride-rich lipoproteins by lipolytic action and thus regulates triglyceride levels in the circulation. 24 Interestingly, the rats that received carrot juice exhibited a reduction of adiposity and leptin content, which corroborated with elevated retinol concentration of the adipose tissue. In line with adiposity reduction, the ingestion of carrot juice or withdrawal of high fructose in the diet normalized hyperinsulinemia and C-peptide levels without impacting the plasma glucose levels, thus reflected in improved insulin sensitivity as indicated by the HOMA-IR index and plasma RBP4 levels; one of the markers of insulin sensitivity.…”

“…23 However, the expression data of these pathway proteins in the liver, such as GPAT1 (lipogenesis), MTTP (lipoprotein secretion) and PT1 (fatty acid β-oxidation), and the plasma β-hydroxy butyrate levels suggest the role of lipoprotein lipase (LPL)-mediated extra-hepatic tissue clearance of plasma triglyceride in regulating hypertriglyceridemia, as the lipoprotein lipase (LPL) present in the vascular bed of adipose tissue and muscle involves in the uptake of triglyceride from the triglyceride-rich lipoproteins by lipolytic action and thus regulates triglyceride levels in the circulation. 24 …”

Chinese Herbal Medicines and Active Metabolites: Potential Antioxidant Treatments for Atherosclerosis

“…However, the location of atherosclerotic lesions in mice is different from that in humans. In the mouse model, plaques locate in the aortic sinus and innominate arteries, while the coronary arteries and carotid arteries are the primary lesions in human ( Zhao et al, 2020b ; Basu and Bornfeldt, 2020 ). The experimental models involved in this review can indeed explain the potential mechanisms of TCM in treating atherosclerosis via antioxidants.…”

Biomarker Discovery in Atherosclerotic Diseases Using Quantitative Nuclear Magnetic Resonance Metabolomics

“…In addition, basic studies suggested that small RLP particles, which contain 5–20 times more cholesterol than LDL, had a greater affinity for subendothelial components. The TRL remnants could be taken up by macrophages directly without modification, thus promoting rapid cholesterol accumulation in lesional macrophages ( 22 , 112 ). TRL remnants are also proposed to exacerbate the atherosclerotic process by inducing the secretion of TNF-α and IL-1β ( 113 ), activating the coagulation cascade ( 114 ), impairing endothelium-dependent vasodilation ( 115 ), and increasing oxidative stress ( 116 ).…”

“…Many large epidemiological studies have supported that triglycerides (TGs) correlate with CVD risk ( 15 – 17 ), although the association is sometimes attenuated with adjustment for other traditional risk factors ( 18 ). However, increasing evidence now has highlighted the importance of triglyceride-rich lipoproteins (TRLs) and their remnants, both in fasting and nonfasting periods ( 19 – 22 ). Populations with mild-to-moderately elevated nonfasting TG levels have increased risks for ischemic stroke, myocardial infarction, ischemic heart disease, and all-cause mortality ( 23 – 25 ).…”