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Obesity and Dyslipidemia

Obesity and Dyslipidemia. AR Esteghamati, MD Associate Professor of Internal Medicine Endocrinology and Metabolism Research Center Tehran University of Medical Sciences. Objectives. prevalence of obesity Hyperlipidemia as a CVD Risk factors Normal lipid metabolism

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Obesity and Dyslipidemia

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  1. Obesity and Dyslipidemia AR Esteghamati, MD Associate Professor of Internal Medicine Endocrinology and Metabolism Research Center Tehran University of Medical Sciences

  2. Objectives • prevalence of obesity • Hyperlipidemia as a CVD Risk factors • Normal lipid metabolism • Obesity-associated dyslipidemia • Lipid composition in obesity

  3. prevalence of obesity • Obesity in the US exceeds 30%, Highest rate • Leading public health problem • From 1980 to 2002, obesity prevalence has doubled in adults • Overweight prevalence has tripled in children and adolescents

  4. Introduction • The dyslipidemia associated with obesity predicts the majority of the increased CV risk seen in obese subjects. The dyslipidemic phenotype, associated with obesity, is characterized by • Increased TG • Decreased HDL • Shift in LDL to a more pro-atherogenic small dense LDL.

  5. CVD Risk factorsLOW HDL • All components of the obesity-associated dyslipidemia have been linked with increased CV risk, but low HDL has emerged as one of the most potent risk factors. • The strong inverse relationship between HDL-c and the incidence of CV disease has been substantiated in numerous large observational studies.

  6. HDL Role in reverse cholesterol transport • Even if LDL-c are lowered < 70 mg-dl, low HDL-c is still associated with an increased CVD risk. • This atheroprotective effect of HDL is attributed to the role of HDL-c in the reverse cholesterol transport (RCT) pathway • Resulting in cholesterol transport from peripheral tissues to the liver followed by excretion in the feces.

  7. HDL Reverse cholesterol Transport

  8. HDL protective effects Inhibition of • Thrombosis • Oxidation • Inflammation

  9. TG as a CVD risk • High-fasting TGs have been shown to have independent predictive value for CV risk even after adjusting for HDL-c levels.

  10. TG as a CVD risk • meta-analysis of 21 population-based prospective studies involving 65,863 men and 11,089 women Each 1-mmol/L (89-mg/dL) TG increase was associated with : • 32% increase in CHD risk in men ( RR 1.30; 95% CI, 1.25–1.35) • 76% increase in women (RR 1.69; 95% CI, 1.45–1.97).

  11. TG as a CVD risk • After adjustment for total cholesterol, LDL-c, HDL-c, BMI, BP, and DM, the increase in CHD risk associated with each 1-mmol/L increase in TG remained statistically significant: • 12% in men (RR 1.12; 95% CI, 1.06–1.19) • 37% in women (RR 1.37; 95% CI, 1.13–1.66)

  12. Small dense LDL • Subjects with high TG are characterized by a shift toward small dense LDL. • Small dense LDLs are Proatherogenic • More likely to be glycosylated and oxidized • important in the initiating process of atherosclerosis

  13. Normal lipid metabolism

  14. Normal lipid metabolism • Cholesterol and TGs are both essential for: • Membrane integrity and structure • Energy source • Signaling molecules • Because they are water-insoluble, cholesterol and TGs have to be transported in special water-soluble particles, such as lipoproteins.

  15. General Structure of Lipoproteins • major lipids of the lipoproteins : cholesterol, triglycerides, and phospholipids. • the apolipoproteins : A family of proteins that occupies the surface of the lipoproteins; play crucial roles in the regulation of lipid transport and lipoprotein metabolism. • the core of the lipoproteins : Triglycerides and the esterified form of cholesterol (cholesteryl esters) ; nonpolar lipids that are insoluble in aqueous environments (hydrophobic) . • the surface of the particles : Phospholipids and a small quantity of free (unesterified) cholesterol ; soluble in both lipid and aqueous environments (amphipathic) ; they act as the interface between the plasma and core components.

  16. Lipoprotein Structure

  17. Normal lipid metabolism • Triglyceride-rich lipoproteins are secreted in the circulation either by • Gut (as chylomicrons) • by the liver VLDL • After a meal, dietary TGs are first digested by pancreatic lipase before they can be absorbed by the intestine and transported into the circulation as chylomicrons.

  18. Chylomicrone Chylomicrons transport the TGs to target tissues adipose tissue muscle hydrolyzed by the enzyme LPL located on the endothelial surface. Upon hydrolysis of TGs, nonesterified fatty acids (NEFA) are formed taken up by adipose tissue for storage or by skeletal muscle for use as an energy source.

  19. LPL activity

  20. Normal lipid metabolism • The LPL involved in this process is mainly produced by adipose tissue and muscle • LPL synthesis and function are under control of insulin. • This control mechanism through insulin in fed state results in: • Activation of LPL in adipose tissue • Decrease in LPL activity in muscle

  21. LDL Chylomicron

  22. Fasted state Body relies on fatty acids as an energy source Glucagon signals the breakdown of TGs by hormone-sensitive lipase (HSL) to release NEFA.

  23. De novo lipogenesis • Under the influence of insulin • liver itself is also able to produce TGs from fatty acids and glycerol • secreted into the blood as VLDL

  24. De novo lipogenesis • The fatty acids used by the liver for TG formation are either derived from • plasma • newly formed within the liver by a process called de novo lipogenesis (DNL).

  25. De novo lipogenesis • In DNL, glucose serves as a substrate for fatty acid synthesis. • The uptake of fatty acids in the liver from the plasma is uncontrolled and driven by FFA plasma levels.

  26. Surplus dietary intake If the liver is taking up more fatty acids than it can use in the VLDL formation and excretion these surplus fatty acids will be stored in the liver in the form of fat droplets. • more dietary TGs (chylomicrons), fatty acids, and glucose (source for VLDL) intake can promote liver fat accumulation.

  27. Insulin role during fed state • up-regulating LPL • stimulation of gene expression of multiple intracellular lipogenic enzymes • Controls uptake and processing of NEFA in adipose tissue and muscle during the fed state.

  28. Insulin role during fed state • Insulin also acts in the liver on the sterol regulatory element binding protein (SREBP) 1-c • located on hepatocyte cell membranes which transcriptionallyactivates most genes involved in DNL

  29. Dietary fats Bile acids+cholesterol Macrophage LDL receptoe LDL receptoe Extrahepatic tissues Intestine HDL receptoe B100 Remnant receptoe LDL B48 E B48 E E E B100 CM B100 CMr VLDL IDL HDL cII cII Liver,steroid-secreting cells Apo B100 LPL LPL Apo B48 Apo CII Apo E capillaries capillaries Endogenous pathway Exogenous pathway

  30. Obesity-associated dyslipidemia

  31. Obesity-associated dyslipidemia • Lipid changes in obesity are similar to those in type-2 DM or IR. • IR is a hallmark of METs, and has an impact on lipid profiles seen in patients with METs. • The presence of IR has also been shown to precede the onset of dyslipidemia in most obese individuals.

  32. Insulin resistance state Reduced efficiency of insulin: • To inhibit HGP • To stimulate glucose use in skeletal muscle and adipose tissue leads to hyperglycemia and a compensatory hyperinsulinemia. • In IR, insulin is not capable of inhibiting TG-lipolysis by HSL in fat stores.

  33. Insulin resistance state • So, flux of FFAs to the liver increases profoundly, and this will contribute to increased fat accumulation within the liver. • IR also results in impaired activation of LPL within the vasculature, contributing to a further increase in circulating TG.

  34. Insulin resistance state • Responses of both LPL and HSL are blunted • Resulting inefficient trapping of dietary energy will produce a postprandial lipemia • increase in NEFA, as is seen in both obesity and hyperinsulinemia.

  35. Insulin resistance state • This increase in NEFA will result in an increased NEFA flux to tissues, like the liver and muscle, during the fed state. • The liver will be the major recipient of this increased flux because of the uncontrolled plasma level-driven uptake.

  36. Insulin resistance state • To maintain TG homeostasis, VLDL production is increased in the liver • particularly large VLDL1 particles , as is also observed in obese- and IR patients

  37. Non Alcoholic Fatty Liver Disease • When plasma NEFA are raised in normal individuals, VLDL secretion will increase. • The formation and excretion of VLDL is then the consequential rate-limiting step and the newly synthesized, but not excreted surplus TGs, will therefore be stored as lipid droplets in the liver that ultimately might lead to nonalcoholic fatty liver disease.

  38. Non Alcoholic Fatty Liver Disease • NAFLD has numerous causes, but is often encountered in patients with obesity or other components of the metabolic syndrome. • The prevalence of NAFLD increases to • 74% in obese • 90%in morbidly obese individuals

  39. Hyperinsulinemia • Hyperinsulinemia per se is also capable of: stimulating DNL in the liver through activation of the previously described SREBP-1 pathway.

  40. Hyperglycemia induced lipogenesis • Hyperglycemia resulting from the IR can also stimulate lipogenesis directly by activation of the carbohydrate response element-binding protein • which in its turn activates the transcription of numerous genes also involved in DNL

  41. Lipid composition in obesity

  42. Lipid composition in obesity • Hypertriglyceridemia due to: • increased assembly, secretion • decreased clearance of VLDL contribute to lower HDL-c levels

  43. Lipid composition in obesity • This results partly from the decreased flux of apolipoproteins and phospholipids from chylomicrons and VLDL particles • which are normally used in HDL-c maturation.

  44. HDL

  45. HDL Reverse cholesterol Transport

  46. CETP activity in obesity • in obese patients the mass and activity of cholesteryl ester transfer protein, are increased • CETP is also secreted by adipose tissue, which is an important source of plasma CETP in human beings.

  47. LCAT mediates the transfer of linoleate from lecithin to free cholesterol on the surface of HDL to form cholesteryl esters that are then transferred to VLDL and eventually LDL. Excess free cholesterol in tissues FC FC FC Apo E Apo AI is a cofactor for esterification of free cholesterol by LCAT. Deficiency of LCAT can be caused by mutations in the enzyme or in Apo A1. LCAT deficiency causes low levels of cholesteryl esters and HDL Pre-HDL HDL3 HDL2 HDL1(HDL-E) LCAT LCAT LCAT Hepatic Lipase TG FC,phosphlipid, apo-A1 Phosphlipid TG CE CETP CM Remnants INTESTINE VLDL IDL Remnant VLDL LDL receptor

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