Obesity and Atherogenic Dyslipidemia
Section snippets
Epidemiology of Atherogenic Dyslipidemia and Relationship to CHD
Atherogenic dyslipidemia, characterized primarily by elevated triglycerides and low HDL-C, is a phenotype associated with increased cardiovascular risk. Most evidence suggests that elevated fasting TG are, in fact, an independent risk factor for CHD.5, 6 For example, fasting serum TG was independently associated with incidence of CHD in the Paris Prospective Study,7 the Prospective Cardiovascular Munster study,8 and the Copenhagen Male Study.9 Multivariate analyses that adjust for HDL-C,
Uptake of Lipoprotein-Derived Fatty Acids and Their Storage by Adipose Tissue
Adipose tissue is responsible for the coordinated uptake, storage, and release of energy in the form of triglycerides (storage) and fatty acids (uptake and release). Adipose acquires dietary fatty acids via the metabolism of triglyceride-rich lipoproteins (TRL), specifically chylomicrons. Lipids ingested via the diet are hydrolyzed within the intestinal lumen by lipases, and nonesterified fatty acids (NEFA) are transported into the enterocytes of the proximal small intestine (Figure 1). Fatty
Pathophysiology of Impaired Fatty Acid Trapping and Storage by Adipose Tissue
Obesity and adipose insulin resistance are associated with impaired adipocyte trapping of fatty acids and excessive adipocyte lipolysis, both of which lead to increased circulating NEFAs relative to tissue requirements. As described in greater detail in the information to follow, this increased flux of NEFA from adipose tissue leads to increased uptake of NEFA by the liver, increased hepatic lipogenesis, increased hepatic very low density lipoprotein (VLDL) TG production, and atherogenic
Hepatic Overproduction of VLDL in Obesity and Insulin Resistance
Elevation in apoB-containing lipoproteins, particularly TRL, is a common feature of obesity and insulin resistance.55 It is of obvious interest to understand the mechanisms linking obesity to elevation in TRL. Kinetic studies have consistently demonstrated that obesity and insulin resistance are associated with increased production of VLDL-TG, and in some cases, VLDL apoB.55 Thus, the mechanisms leading to VLDL overproduction in obesity and insulin resistance are of great interest. A major
Pathophysiology of Low HDL Cholesterol in Obesity
Low levels of HDL-C are very common in obesity.63 However, despite this common clinical observation, the mechanisms of reduced HDL-C in obese and insulin-resistant states are poorly understood. One causal factor is certainly the elevated levels of triglyceride-rich lipoproteins as previously discussed. There is substantial interaction between TRL and HDL in their metabolism (Figure 4). With the hydrolysis by LPL of chylomicron and VLDL triglycerides and shrinkage of the particles, excess
Conclusion
Atherogenic dyslipidemia is extremely common in obesity, both in the presence and absence of overt insulin resistance and is likely to be a major factor in the increased risk of cardiovascular disease in these individuals. A thorough understanding of the molecular mechanisms is critical to furthering our understanding of the influence of obesity on lipoprotein metabolism and to the development of appropriate therapeutic approaches. It is interesting to note that pharmacological targeting of
References (111)
- et al.
Hypertriglyceridemia as a cardiovascular risk factor
Am J Cardiol
(1998) - et al.
High density lipoprotein as a protective factor against coronary heart diseaseThe Framingham Study
Am J Med
(1977) - et al.
HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study
Atherosclerosis
(2000) - et al.
Distribution of lipids in 8,500 men with coronary artery disease
Am J Cardiol
(1995) - et al.
Gender and racial differences in lipoprotein subclass distributions: the STRRIDE study
Atherosclerosis
(2004) - et al.
Evaluation of Lp[a] and other independent risk factors for CHD in Asian Indians and their USA counterparts
J Lipid Res
(2001) - et al.
Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE)
The Lancet
(2000) - et al.
Non-obese (body mass index < 25 kg/m2) Asian Indians with normal waist circumference have high cardiovascular risk
Nutrition
(2003) Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis
J Lipid Res
(1996)- et al.
Lipoprotein lipase: genetics, lipid uptake, and regulation
J Lipid Res
(2002)
Metabolism of lipids in human white adipocyte
Diabetes Metab
DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis
J Biol Chem
Lipopenia and skin barrier abnormalities in DGAT2-deficient mice
J Biol Chem
Novel roles for acylation stimulating protein/C3adesArg: a review of recent in vitro and in vivo evidence
Vitam Horm
Human fat cell lipolysis: biochemistry, regulation and clinical role
Best Pract Res Clin Endocrinol Metab
Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis
J. Lipid Res
Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome
Pharmacol Res
The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target
Trends Pharmacol Sci
(D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G
J Biol Chem
Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue
J Lipid Res
Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis
J Biol Chem
Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis
J Biol Chem
Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities
J Biol Chem
Lipid metabolism in omental adipose tissue during operative surgery
J Surg Res
Enhancement of serum lipoprotein lipase mass levels by intensive insulin therapy
Diabetes Res Clin Pract
Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance
Trends Cardiovasc Med
Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins
J Biol Chem
A deficiency of microsomal triglyceride transfer protein reduces apolipoprotein B secretion
J Biol Chem
Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B
J Lipid Res
Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression
J Lipid Res
The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states
J Diabetes Comp
Preferential expression of cholesteryl ester transfer protein mRNA by stromal-vascular cells of human adipose tissue
Biochim Biophys Acta
Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: relationship to cell size and membrane cholesterol content
J Lipid Res
Relationship of adipose tissue cholesteryl ester transfer protein (CETP) mRNA to plasma concentrations of CETP in man
Atherosclerosis
Induction of cholesteryl ester transfer protein in adipose tissue and plasma of the fructose-fed hamster
Life Sci
Clearance of postprandial and lipolytically modified human HDL in rabbits and rats
J Lipid Res
Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet
J Lipid Res
Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey
JAMA
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines
Circulation
The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study
Diabetes Care
Metabolic syndrome and cardiovascular disease in older people: the cardiovascular health study
J Am Geriatr Soc
Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies
J Cardiovasc Risk
Is the level of serum triglyceride a significant predictor of coronary death in “normocholesterolemic” subjects?The Paris Prospective Study
Am J Epidemiol
The emergence of triglycerides as a significant independent risk factor in coronary artery disease
Eur Heart J
Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study
Circulation
High-density lipoproteins—the clinical implications of recent studies
N Engl J Med
Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: A 21-year follow-up of 8000 men
Arterioscler Thromb Vasc Biol
Diabetes, hyperlipidemia, and coronary artery disease
Am J Cardiol
BMI does not accurately predict overweight in Asian Indians in northern India
Br J Nutrition
Responses to eating: lipoproteins, lipolytic products and atherosclerosis
Curr Opin Lipidol
Cited by (124)
Multi-omics analysis reveals the mechanism of Lacticaseibacillus paracasei IMAUJBC1 in alleviating hyperlipidemia
2024, Journal of Functional FoodsFood protein-derived bioactive peptides for the management of nutrition related chronic diseases
2022, Advances in Food and Nutrition ResearchReference values for the triglyceride to high-density lipoprotein ratio and its association with cardiometabolic diseases in a mixed adult population: The ELSA-Brasil study
2021, Journal of Clinical LipidologyCitation Excerpt :Moreover, the definition of a TG/HDL-C reference value goes beyond its ability to detect individuals with cardiometabolic conditions. The so-called atherogenic dyslipidemia is highly frequent due to the obesity epidemics and favors the development of atherosclerosis.33 Also, the TG/HDL-C ability to predict insulin resistance, which is not easily diagnosed by the currently used methods (mainly based on insulin levels detection), supports this ratio as an important cardiometabolic risk predictive marker.34
Dysregulation of microRNA-125a contributes to obesity-associated insulin resistance and dysregulates lipid metabolism in mice
2020, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Dr Bamba is supported by a grant from the Lawson Wilkins Pediatric Endocrine Society and a National Institutes of Health T32 Diabetes Research Grant, DR 63688-03. Dr Rader has been supported by a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, a Doris Duke Charitable Foundation Distinguished Clinical Scientist Award, as well as grants from the National Heart, Lung, and Blood Institute (HL55323, HL70128, HL22633), National Institute of Diabetes and Digestive and Kidney Diseases (DK59533, DK06990), and the National Center for Research Resources (Mol-RR00040).