Obesity and Atherogenic Dyslipidemia

doi:10.1053/j.gastro.2007.03.056

Gastroenterology

Volume 132, Issue 6, May 2007, Pages 2181-2190

https://doi.org/10.1053/j.gastro.2007.03.056 Get rights and content

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.

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)

M.A. Austin et al.
Hypertriglyceridemia as a cardiovascular risk factor
Am J Cardiol
(1998)
T. Gordon et al.
High density lipoprotein as a protective factor against coronary heart diseaseThe Framingham Study
Am J Med
(1977)
J.P. Despres et al.
HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study
Atherosclerosis
(2000)
H.B. Rubins et al.
Distribution of lipids in 8,500 men with coronary artery disease
Am J Cardiol
(1995)
J.L. Johnson et al.
Gender and racial differences in lipoprotein subclass distributions: the STRRIDE study
Atherosclerosis
(2004)
R.C. Hoogeveen et al.
Evaluation of Lp[a] and other independent risk factors for CHD in Asian Indians and their USA counterparts
J Lipid Res
(2001)
S.S. Anand 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)
N.K. Vikram et al.
Non-obese (body mass index < 25 kg/m²) Asian Indians with normal waist circumference have high cardiovascular risk
Nutrition
(2003)
I.J. Goldberg
Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis
J Lipid Res
(1996)
M. Merkel et al.
Lipoprotein lipase: genetics, lipid uptake, and regulation
J Lipid Res
(2002)

V. Large et al.

Metabolism of lipids in human white adipocyte

Diabetes Metab

(2004)

K.K. Buhman et al.

DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis

J Biol Chem

(2002)

S.J. Stone et al.

Lipopenia and skin barrier abnormalities in DGAT2-deficient mice

J Biol Chem

(2004)

M. Maslowska et al.

Novel roles for acylation stimulating protein/C3adesArg: a review of recent in vitro and in vivo evidence

Vitam Horm

(2005)

P. Arner

Human fat cell lipolysis: biochemistry, regulation and clinical role

Best Pract Res Clin Endocrinol Metab

(2005)

F.B. Kraemer et al.

Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis

J. Lipid Res

(2002)

D. Langin

Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome

Pharmacol Res

(2006)

S. Offermanns

The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target

Trends Pharmacol Sci

(2006)

A.K. Taggart et al.

(D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G

J Biol Chem

(2005)

R. Zimmermann et al.

Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue

J Lipid Res

(2003)

G. Haemmerle et al.

Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis

J Biol Chem

(2002)

J.A. Villena et al.

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

(2004)

C.M. Jenkins et al.

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

(2004)

J.S. Samra et al.

Lipid metabolism in omental adipose tissue during operative surgery

J Surg Res

(2005)

Y. Miyashita et al.

Enhancement of serum lipoprotein lipase mass levels by intensive insulin therapy

Diabetes Res Clin Pract

(2006)

K. Adeli et al.

Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance

Trends Cardiovasc Med

(2001)

E.A. Fisher et al.

Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins

J Biol Chem

(2002)

G.K. Leung et al.

A deficiency of microsomal triglyceride transfer protein reduces apolipoprotein B secretion

J Biol Chem

(2000)

U.J.F. Tietge et al.

Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B

J Lipid Res

(1999)

M.C. Lin et al.

Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression

J Lipid Res

(1995)

S. Rashid et al.

The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states

J Diabetes Comp

(2002)

T. Radeau et al.

Preferential expression of cholesteryl ester transfer protein mRNA by stromal-vascular cells of human adipose tissue

Biochim Biophys Acta

(1998)

T. Radeau et al.

Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: relationship to cell size and membrane cholesterol content

J Lipid Res

(1995)

T. Radeau et al.

Relationship of adipose tissue cholesteryl ester transfer protein (CETP) mRNA to plasma concentrations of CETP in man

Atherosclerosis

(1998)

P. Remillard et al.

Induction of cholesteryl ester transfer protein in adipose tissue and plasma of the fructose-fed hamster

Life Sci

(2001)

G.F. Lewis et al.

Clearance of postprandial and lipolytically modified human HDL in rabbits and rats

J Lipid Res

(1997)

S.S. Deeb et al.

Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet

J Lipid Res

(2003)

E.S. Ford et al.

Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey

JAMA

(2002)

S.M. Grundy et al.

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines

Circulation

(2004)

A.M. McNeill et al.

The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study

Diabetes Care

(2005)

A.M. McNeill et al.

Metabolic syndrome and cardiovascular disease in older people: the cardiovascular health study

J Am Geriatr Soc

(2006)

J.E. Hokanson et al.

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

(1996)

F. Cambien et al.

Is the level of serum triglyceride a significant predictor of coronary death in “normocholesterolemic” subjects?The Paris Prospective Study

Am J Epidemiol

(1986)

G. Assmann et al.

The emergence of triglycerides as a significant independent risk factor in coronary artery disease

Eur Heart J

(1998)

J. Jeppesen et al.

Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study

Circulation

(1998)

D.J. Gordon et al.

High-density lipoproteins—the clinical implications of recent studies

N Engl J Med

(1989)

U. Goldbourt et al.

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

(1997)

S.M. Haffner

Diabetes, hyperlipidemia, and coronary artery disease

Am J Cardiol

(1999)

V. Dudeja et al.

BMI does not accurately predict overweight in Asian Indians in northern India

Br J Nutrition

(2001)

I.J. Goldberg et al.

Responses to eating: lipoproteins, lipolytic products and atherosclerosis

Curr Opin Lipidol

(2000)

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Citation 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
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To define sex- and ethnicity-specific reference values for TG/HDL-C ratio in a large sample of healthy multiethnic adults and test its association with cardiometabolic conditions.
An apparently healthy sample (n = 2,472), aged 35–74, free of major cardiovascular risk factors, was used to generate the reference values for the TG/HDL-C. Exclusion criteria were diabetes, elevated blood pressure, obesity, hypercholesterolemia, severe hypertriglyceridemia, and smoking history. Cut-offs based on the reference values were tested in the whole ELSA Brasil study (n = 13,245), stratified by sex and ethnicity, to identify cardiometabolic conditions.
TG/HDL-C ratio was higher in men than women, and did not change significantly with age, regardless of sex and ethnicity. Also, black individuals showed lower levels of TG/HDL-C as compared to other ethnic groups. ROC curve showed that the cut-off based on the 75th percentile displayed better sensitivities and specificities for men and women, regardless of ethnicity. Also, the sex- and ethnicity-specific cut-offs based on the 75th percentile were significantly associated with all tested cardiometabolic conditions (hypertension, diabetes, obesity, metabolic syndrome, and insulin resistance). Also, we observed that the use of a single sex-specific cut-off (men: 2.6; women: 1.7) could be used for the different ethnicities with good reliability.
The defined TG/HDL-C cut-offs (men: 2.6; women: 1.7) are reliable and showed good clinical applicability to detect cardiometabolic conditions in a multiethnic population.
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: 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).

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Obesity and Atherogenic Dyslipidemia

Section snippets

Epidemiology of Atherogenic Dyslipidemia and Relationship to CHD

Uptake of Lipoprotein-Derived Fatty Acids and Their Storage by Adipose Tissue

Pathophysiology of Impaired Fatty Acid Trapping and Storage by Adipose Tissue

Hepatic Overproduction of VLDL in Obesity and Insulin Resistance

Pathophysiology of Low HDL Cholesterol in Obesity

Conclusion

Am J Cardiol

Am J Med

Atherosclerosis

Am J Cardiol

Atherosclerosis

J Lipid Res

The Lancet

Nutrition

J Lipid Res

J Lipid Res

Diabetes Metab

J Biol Chem

J Biol Chem

Vitam Horm

Best Pract Res Clin Endocrinol Metab

J. Lipid Res

Pharmacol Res

Trends Pharmacol Sci

J Biol Chem

J Lipid Res

J Biol Chem

J Biol Chem

J Biol Chem

J Surg Res

Diabetes Res Clin Pract

Trends Cardiovasc Med

J Biol Chem

J Biol Chem

J Lipid Res

J Lipid Res

J Diabetes Comp

Biochim Biophys Acta

J Lipid Res

Atherosclerosis

Life Sci

J Lipid Res

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