MargiAnne Isaia, MD MPH Advanced Nutrition Diet and Dyslipidemia

DIET AND DYSLIPIDEMIA DYSLIPIDEMIA Abnormal blood lipid levels Blood Lipids HDL-C, Triglyceride, TG Small dense LDL-C, Oxidized LDL-C, Lipoprotein (a), Lp(a) Dyslipidemia Asymptomatic patients Symptomatic patients Dyslipidemia Primary causes Secondary causes

BLOOD LIPID VALUES Total Cholesterol < 200 mg/dL: desirable mg/dL: borderline-high risk ≥ 240 mg/dL: high risk LDL-C < 100 mg/dL: optimal mg/dL: near optimal/ above optimal mg/dL: borderline high mg/dL: high ≥ 190 mg/dL: very high HDL-C ≥ 60 mg/dL: desirable < mg/dL: undesirable DIET AND DYSLIPIDEMIA

BLOOD LIPID VALUES Triglyceride < 150 mg/dL : normal mg/dL : borderline high mg/dL : high > 500 mg/dL : very high LDL: HDL ratio low risk : < 3.5 average risk : increased risk : > 5.0 Total Cholesterol: HDL ratio low risk : < 3.3 women, < 3.4 men average risk : increased risk : > DIET AND DYSLIPIDEMIA

DIET AND DYSLIPIDEMIA

LIFESTYLE MODIFICATIONS Patient has dyslipidemia or is at risk for CHD initiate Lifestyle modifications Secondary causes and conditions associated with Hyperlipidemia considered and treated Diet and exercise cornerstones of treatment Therapeutic Lifestyle Changes Program and Individualized program of regular exercise Calculate 10-year risk for CHD or add up cardiac risk factors Lifestyle interventions ± Pharmacologic therapy DIET AND DYSLIPIDEMIA

DIET AND DYSLIPIDEMIA

LIFESTYLE MODIFICATIONS Diet Aerobic exercise Weight management Smoking cessation Evaluation of alcohol consumption Functional food: stanol/sterols – 2g/d, VLC n-3 PUFA : EPA+DHA 1 g/d Vitamin E supplements should not be used: no benefit in preventing clinical outcomes DIET AND DYSLIPIDEMIA

HDL-C Dietary fiber - slightly decreases HDL-C - the overall ratio of LDL-C: HDL-C is still low - mechanism no clear maybe overall decrease in Total Cholesterol (decreased “de novo” Cholesterol synthesis) Dietary Cholesterol - increases HDL-C - mechanism overall increase in Total Cholesterol DIET AND DYSLIPIDEMIA

LIVER CELL: TG and Cholesterol are included in Nascent VLDL-C DIET AND DYSLIPIDEMIA

HDL-C HDL-C and Triglyceride inversely related Diet no distinctly pronounced effect on HDL-C If TG decreases, HDL-C increases If dietary factors increase TG, HDL-C will decrease Exercise increases HDL-C DIET AND DYSLIPIDEMIA

HDL-C Saturated fat - increases HDL-C - LDL-C: HDL-C ratio still high with SFA - Stearic Acid may decrease HDL-C compared to UFA Mechanism reported to be decreased clearance of HDL-C Trans fat - lowers HDL-C - LDL-C: HDL-C ratio is very high - Mechanism lowers Apo A-I promoter Apo A-I gene not expressed – decreased production of Apo A-I Apo A-I activates LCAT DIET AND DYSLIPIDEMIA

DIET AND DYSLIPIDEMIA

HDL-C Trans fat  production of Apo A-I Apo A-I activates LCAT  Trans fat   HDL-C DIET AND DYSLIPIDEMIA

HDL-C MUFA - when MUFA replaces CHO it increases HDL- C - Step II diet versus Mediterranean diet Step II diet : increased CHO, decreased fat Mediterranean diet: increased MUFA (olive oil) - Increase Apo A-I expression with increased activity of LCAT consequently, Cholesterol Esters increase N-3 PUFA - modestly increased plasma HDL-C or no change - especially EPA and DHA - ALA not as effective in most studies - inversely related to plasma TG (lower TG, indirect effect of N-3 FA) DIET AND DYSLIPIDEMIA

TRIGLYCERIDE Carbohydrates - increases plasma TG - type of CHO more important detrimental than amount - up to 55 % energy from CHO, hyper TG not seen - Sucrose and Fructose main culprits - Resistant starches and dietary fiber prevent TG increase DIET AND DYSLIPIDEMIA

TRIGLYCERIDE Dietary Carbohydrates Refined CHO increases plasma TG Mechanism: Overproduction or poor clearance Insulin resistance - result of chronic exposure to refined CHO - adipose tissue TG hydrolysis causes increased influx of FFA to liver - FFA is converted to TG and packaged as VLDL-C Insulin resistance – (-) activity of Lipoprotein Lipase (Insulin dependent enzyme) - decreased clearance of TG from CM and VLDL-C - more FFA ends up in liver as CM remnants More Fructose and Sucrose (+) lipogenesis in liver Fructose increases lipogenesis more than Glucose does Fatty Acid oxidation is low Malonyl CoA produced during lipogenesis inhibits  -oxidation DIET AND DYSLIPIDEMIA

TRIGLYCERIDE Carbohydrates Fructose causes greater increase than Glucose Mechanism - Insulin independent uptake - By passes PFK-1 regulation in glycolysis PFK-1 rate limiting enzyme the most regulated enzyme in the body - Rapid conversion to Glycerol 3-P and DAP - Backbone for TG synthesis - Acetyl CoA generated from DAP is substrate for TG DAP Dihydroxy Acetone Phosphate DIET AND DYSLIPIDEMIA

Fructose and Dyslipidemia DIET AND DYSLIPIDEMIA

TRIGLYCERIDE  plasma TG   VLDL-TG Exchange with HDL-C using CETP - more TG from VLDL-C goes to HDL-C, more CE goes from HDL-C to IDL-C - HDL-C lowered So TG and HDL-C are inversely related DIET AND DYSLIPIDEMIA

TRIGLYCERIDE MUFA - when it replaces CHO lowers TG - mechanism via improving IS and thus LPL activity and clearance of plasma TG N-3 PUFA - lowers TG (independent effect) - EPA and DHA most effective for CHD - ALA not equivalent DIET AND DYSLIPIDEMIA

TRIGLYCERIDE N-3 PUFA - EPA, DHA at doses of 1 g/d lower TG for patients with hyper TG a higher dose (2-4 g/d) Therapeutic Lifestyle Change TLC Diet - ALA is not effective as EPA+DHA Lowering effect dependent on membrane EPA/DHA saturation incorporation in lipid membrane not known how much ALA is needed to accomplish this Further research: altering ratio of N-6: N-3 and - conversion of ALA to EPA/DHA - incorporation of EPA/DHA into membranes DIET AND DYSLIPIDEMIA

TRIGLYCERIDE N-3 PUFA mechanism of action in improving TG levels - membrane fluidity  membrane fluidity improves Insulin Sensitivity followed by increased action of LPL and clearance of TG from plasma (CM and VLDL-TG) - LPL gene expression PPAR binding to PPRE increases with N-3 PUFA up regulation of LPL gene expression increased LPL and clearance of TG from plasma DIET AND DYSLIPIDEMIA

DIET AND DYSLIPIDEMIA

TRIGLYCERIDE Non-dietary factors that modify effect of diet on plasma TG - Genetics Apo E2 allele subjects marked decrease in TG compared to Apo E3 and Apo E4 alleles - Gender Men greater increase in TG with CHO than women - Exercise increases IS so may blunt effect of CHO - athletes don’t have increased TG - Abdominal adiposity upper body visceral obesity more prone to TG increases with high CHO DIET AND DYSLIPIDEMIA

SMALL DENSE LDL-C LDL-C pattern - large buoyant, pattern A,and small dense pattern B - small dense LDL –C is more atherogenic can sieve through the vascular endothelium more easily so, more prone to lipid peroxidation also known to stimulate inflammatory markers Dietary effects on small dense LDL-C - low-fat, high-CHO diet increases small dense LDL-C especially Fructose increases small dense LDL-C - replacing CHO with MUFA lowers small dense LDL-C N-3 PUFA lowers small dense LDL-C - EPA/DHA, not so much ALA DIET AND DYSLIPIDEMIA

SMALL DENSE LDL-C Small dense LDL –C forms when plasma TG>120 mg/dL The higher the plasma TG, the higher the level of small dense LDL-C - high VLDL-TG - CETP exchange - low HDL-C - high small dense LDL-C DIET AND DYSLIPIDEMIA

OXIDIZED LDL-C Causes - high plasma LDL-C - increased oxidant stress smoking, pollution, alcohol, oxidized food intake, drugs - low antioxidant status low intake of fruits and vegetables low intake of vitamin E, C,  -carotene increased PUFA/vitamin E ratio in diet DIET AND DYSLIPIDEMIA

DIET AND DYSLIPIDEMIA OXIDIZED LDL-C High plasma LDL-C increases entry of LDL-C inside artery walls In plasma LDL-C is protected from oxidation, but trapped LDL-C is not. If increased oxidant stress, there is decrease in anti-oxidants, PUFA and Apo B undergoes changes Oxidized LDL-C (+) expression of adhesion molecules and differentiation of monocyte to macrophage Foam cell formation (atherosclerosis)

OXIDIZED LDL-C Dietary CHO - no effect Dietary Fatty Acids MUFA inhibits LDL-C oxidation mechanism unclear: possibly other protective components in MUFA rich foods (eg.: olive oil) presence of single double bond makes it less prone to oxidation PUFA N-6 PUFA increases LDL-C oxidation more than N-3 PUFA mechanism not clear may be related to total amount in the diet; more N-6 PUFA, therefore more prone to oxidation N-3 PUFA neutral effect mechanism not clear possibly because absolute intake is usually low fish oil supplementation at 2-4 g/d does not increase LDL-C oxidation Added Vitamin E or other antioxidants can help DIET AND DYSLIPIDEMIA

LIPOPROTEIN (A) Lp (a) is LDL-C particle with the Apo B-100 modified chemically The formation of Lp (a) is genetically determined High levels = risk factor for CVD (-)Plasminogen, thus prevent clot lysis Least modifiable with diet Some studies show UFA may lower but not consistent DIET AND DYSLIPIDEMIA

RECOMMENDATIONS Do not exceed 60% energy from CHO unless indicated for special conditions - decrease intake of sugars and refined CHO - include CHO sources high in fiber and resistant starches - limit intake of fructose and High Fructose Corn Syrup Reduce saturated and trans fat Substitute CHO with MUFA Increase N-3 PUFA intake - especially EPA and DHA DIET AND DYSLIPIDEMIA

REFERENCES Lichtenstein AH. Dietary fat, CHO, and protein: effects on plasma Lipoprotein patterns. J Lipid Res,2006, 47: Chong MFF, et al. Metabolic interaction of dietary sugars and plasma Lipids with a focus on mechanisms and de novo lipogenesis Proc Nutr Soc, 2007, 66: Calder PC. N-3 fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci, 2004, 107:

QUESTIONS?