Metabolic defects underlying dyslipidemia in abdominal obesity

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Gerard Williamson
5 years ago
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Division of Cardiology Helsinki University Hospital, Finland

1 Metabolic defects underlying dyslipidemia in abdominal obesity Professor Marja-Riitta Taskinen Department of Medicine, Division of Cardiology Helsinki University Hospital, Finland Disclosures: Honorariums/ Consultant to MSD, Novartis, Kowa, Sanofi-Aventis

Lipid overflow into liver, pancreas, muscle and heart FFA Inflamed

2 What is ectopic fat accumulation? Caloric Intake and/ or Energy Expenditure Positive Energy Balance Lipid overflow into liver, pancreas, muscle and heart FFA Inflamed adipose tissue Imbalance between loading and export of lipids results in ectopic fat accumulation at organs

3 The fatty liver produces most CVD risk factors uc l G e s o V L D L L D H ALT, AST Genetic Predisposition Caloric excess Fat in the diet? Fructose Sucrose The Fatty Liver ; Overproduction of Cardiometabolic Risk Factors Fibrinogen Angiotensinogen CRP, SAA TNF-а, IL-6 FVII, PAI-1

4 Is liver fat the culprit of dyslipidemia? Hepatic steatosis(nafld) is linked to insulin resistance in the liver Hepatic steatosis associates with features of the atherogenic lipid triad Hepatic steatosis associates with intraabdominal obesity

5 Regulation of lipid metabolism in the liver FFA flux Dietary fatty acids DNL Fatty acid oxidation VLDL assembly VLDL secretion

6 Determination of liver fat content using MR spectroscopy water peak Liver fat 6 % Liver fat 23 % triglyceride peak Ryysy L et al. Diabetes, 2000

7 VLDL1 TG production Relationship between VLDL1 production rate and plasma VLDL1 TG pools mg/kg/day 600 r=0.62 p< VLDL1 TG pool, mg/kg VLDL1 TG production rate is the predictor for VLDL1 TG pool size Adiels M et al. ATVB 2005;25:

8 VLDL1 TG production is linked with detrimental changes of LDL size and HDL cholesterol LDL size vs VLDL1 TG production mg/kg/day HDL Chol vs VLDL1 TG production mg/kg/day 600 r=-0.56 p< LDL size, nm r=-0.64 p< HDL Cholesterol, mmol/l Adiels M et al. Diabetologia 2006;49:755-65

9 The relationship between VLDL1 production and liver fat assessed using proton spectroscopy TG VLDL1 production mg/kg/day r=0.58 p< Liver fat % Liver fat content is the driving force for VLDL TG overproduction Adiels M et al. Diabetologia 2006;49:

10 Defective regulation of VLDL metabolism by insulin in Type 2 diabetes patients Oxidation Denovo lipogenesis mg/day FFA 1000 FA Remnants Chol ester Degradation TG VLDL1 apo B production MTP VLDL2 apob IDL LDL LPL HL IDL HL LDL Small dense LDL LPL -51% Controls Type 2 VLDL1 LPL VLDL2 Insulin fails to suppress VLDL1 apo B production Accumulation of VLDL1 particles

11 Characteristics of the subjects Low liver fat (n=10) BMI, kg/m2 Subcutaneous fat, cm2 Intra-abdominal fat, cm2 Liver fat, % M-value, mg kg-1 min-1 F-triglycerides, mmol/l HDL-chol, mmol/l LDL size, nm 26.0± ± ± ± ± ± ± ±0.8 High liver fat (n=10) 28.4± ± ±861* 11.2±4.7*** 4.0±2.1* 2.0± ±0.3** 25.3±1.1** Adiels M et al. Diabetologia 2007;50:

12 High liver fat: lack of VLDL1 suppression in response to insulin Low liver fat <5.5% High liver fat >5.5% % of total VLDL at baseline VLDL1 TG production rate Δ 61% p< Time (min) Adiels M et al. Diabetologia 2007;50:

13 Normal production and regulation of VLDL1 particles in normal healthy subjects Low Liver Fat Insulin TG apob VLDL1 VLDL2 VLDL2 Adiels M et al. Diabetologia 2007;50:

14 Overproduction and dysregulation of VLDL1 particles in Type 2 diabetes High Liver Fat Insulin TG apob VLDL1 VLDL2 VLDL2 High liver fat is linked with hepatic insulin resistance and overproduction of large VLDL particles Adiels M et al. Diabetologia 2007;50:

15 Sources of fatty acids for liver and VLDL-TG FFA POOL 2 CM 2 TG DNL GLUCOSE 3 1 FA STORAGE? β-ox 4 LIVER TG ApoB 5 VLDL TG INSULIN Adiels M et al. ATVB, 2008;28;

Whole-body palmitate rate of appearance in obese subjects without and with NAFLD Palmitate RA (µmol/min) (n=14 in both groups) 160 NAFLD * 120 Normal IHTG 80 40 0 Liver fat % BMI

16 Whole-body palmitate rate of appearance in obese subjects without and with NAFLD Palmitate RA (µmol/min) (n=14 in both groups) 160 NAFLD * 120 Normal IHTG Liver fat % BMI (kg/m2) 3.4 ± ± ± ± 1.2 The rate of the release of fatty acids from AT is increased in obese subjects with NAFLD Fabbrini E et al. Gastroenterology 2008;134:

VLDL-TG secretion rate is increased in obese subjects with NAFLD Non-systemic fatty acids 30 * Systemic plasma FFA (µmol/min) 25 20 15 10 5 0 Liver fat % BMI (kg/m2) * 3.4 ± 0.4 35.3 ± 1.

17 VLDL-TG secretion rate is increased in obese subjects with NAFLD Non-systemic fatty acids 30 * Systemic plasma FFA (µmol/min) Liver fat % BMI (kg/m2) * 3.4 ± ± ± ± 1.2 Fatty acids derived from nonsystematic sources are the major factors responsible for the increase in VLDL-TG secretion Fabbrini E et al. Gastroenterology 2008;134:

18 Sources of fatty acids for liver fat and VLDL-Triglycerides Increased rate of FFA flux from AT results in increased rate of hepatic FFA uptake Intrahepatic DNL is enhanced in subjects with NAFLD The production and secretion of large VLDL particles correlates with liver fat content Basal hepatic lipid oxidation seems to be unaltered in subjects with NAFLD Overproduction of VLDL particles is NOT able to adequately compensate for increase of hepatic TG production liver fat accumulation

19 Regulation of DNL by SREBP1-C, ChREBP and LXRs in liver Insulin signaling pathway Glucose signaling pathway LXR LXR? SREBP ? ChREBP GK L-PK ACC FAS ELOVL-6 SCD-1 GPAT DGAT ?? TG Postic C and Girard J. J Clin Invest 2008;118:

20 Imbalance of liporegulation; the culprit of fatty liver and dyslipidemia Insulin resistance/ Hyperinsulinemia Inflamed adipose tissue FFA flux Excess dietary fat De Novo lipogenesis ECS dysregulation Lipid oxidation VLDL Atherogenic dyslipidemia

21 Why do not all people with a big waist have dyslipidemia? Elevated VLDL1 concentrations Insulin resistance Normal lipid profile Visceral obesity Insulin resistance Visceral obesity Low HDL The atherogenic triad Small, dense LDL particles

22 My warmest thanks for my collaborators Current players Gothenburg The ladies of the lab Imaging Team Anne Hiukka Aino Soro-Paavonen Sanni Söderlund Jukka Westerbacka Hannele Yki-Järvinen Hannele Hilden Virve Naatti Helinä Perttunen-Nio Martin Adiels Jan Boren Sven-Olof Olofsson Nina Lundbom Jesper Lundbom Antti Hakkarainen

Role of apolipoprotein B-containing lipoproteins in the development of atherosclerosis Jan Borén MD, PhD

Role of apolipoprotein B-containing lipoproteins in the development of atherosclerosis Jan Borén MD, PhD Our laboratory focuses on the role of apolipoprotein (apo) B- containing lipoproteins in normal