HBG 13 ( Cholesterol and Lipoprotein)

• Physiological functions of cholesterol in the body:

  • Essential component of animal cell membranes
  • Precursor of steroid hormones and bile salts
  • Precursor of vitamin D
  • Not required in the human diet because our cells can synthesize cholesterol de novo
• Cholesterol biosynthesis from acetyl CoA:

  • The pathway is located in the cytosol, beginning with acetyl-CoA
  • Most cells can make cholesterol, but the liver is the most active
  • All 27 carbon atoms of cholesterol are derived from the acetate moiety of acetyl CoA
  • Cholesterol synthesis can be divided into 3 phases: Conversion of acetyl CoA to HMG-CoA, Conversion of HMG-CoA to squalene, Conversion of squalene to cholesterol
• HMG CoA reductase and its role in the control of cholesterol synthesis:

  • Integral membrane protein in the ER
  • Carries out an irreversible reaction
  • Important regulatory enzyme/rate-limiting step in cholesterol synthesis
  • NADPH dependent
  • Activity is reduced by feeding of cholesterol, fasting, and reversible phosphorylation-dephosphorylation
  • Insulin stimulates HMG CoA reductase activity, while glucagon antagonizes the effect of insulin and thyroid hormone stimulates HMG CoA reductase activity
• Cholesterol transport in the blood and equilibrium in lipoproteins and cell membrane:

  • Cholesterol is transported in lipoproteins and stored as cholesterol ester
  • The hydroxyl group of cholesterol is oriented towards the aqueous phase in bilayer membranes
  • The hydroxyl group is commonly esterified to a fatty acid for transport in lipoproteins and for storage
• Conversion of cholesterol to bile acids and control of cholesterol 7-hydroxylase:

  • Bile acids are synthesized from cholesterol in the liver and stored in the gall bladder
  • Enterohepatic circulation involves the conversion of primary bile acids to secondary bile acids by intestinal bacteria
  • Bile acids serve multiple functions, including eliminating cholesterol from the body and aiding in the reduction of bacteria flora in the small intestine and biliary tract
  • About 800 mg of cholesterol is produced per day, with about half used for bile acid synthesis
• Types of blood lipoproteins:

  • Chylomicrons
  • VLDL
  • IDL
  • LDL
  • HDL
• Regulation of Cholesterol Production:

  • Cholesterol biosynthesis is stimulated when the diet is low in cholesterol
  • An important mechanism for disposing of cholesterol is conversion to bile acids
  • Statins inhibit HMG-CoA reductase, reducing cholesterol and VLDL synthesis in the liver
  • Statins are effective for treating dyslipidemia, except when LDL receptor dysfunctional
• Clinical correlations:

  • Cholesterol gallstone
  • Cholesterol link to atherosclerosis
  • Cardiovascular diseases
  • Clinical significance of LDL: HDL ratio in relation to coronary heart disease
  • Hypo- and hyper-lipoproteinemia
• Physiologic importance of lipids:

  • Source of energy (triglycerides → free fatty acids)
  • Typical daily intake of lipids: ~80 - 100 g/d
  • Adipose tissue represents ~1/5 of body weight in lean subjects, serving as a ~570000 kJ energy store (enough for ~3 months of complete starvation)
  • Building material for the synthesis of many compounds
  • Cholesterol:
  • Typical daily intake: ~200 - 500 mg/d
  • Functions as signalling molecules (steroid hormones, vitamin D, prostaglandins, enzyme cofactors)
  • Components of plasma membranes (phospholipids and cholesterol)
  • Bile acids
• Concentration of lipoproteins in plasma is influenced by genetic factors and the environment

  • Hyperlipoproteinemia (HLP)/dyslipidemia (DLP) are metabolic diseases characterized by increased/decreased levels of certain lipids and lipoproteins in plasma due to various factors
• Lipoproteins are macromolecular complexes consisting of proteins (apolipoproteins, enzymes) and lipids (cholesterol, cholesterol ester, triglycerides, phospholipids)

  • Intestine-derived lipoproteins: chylomicrons
  • Liver-derived lipoproteins: VLDL, IDL, LDL, HDL
  • Circulating lipoproteins have different compositions and metabolic fates
• Apolipoproteins:

  • Control the metabolic fate of lipoproteins
  • Functions include activation of lipolytic enzymes, recognition by receptors, and participation in lipid exchange between particles
  • Different types in various lipoproteins
  • Atherogenic particles contain apoB (apoB-100 or apoB-48)
• Lipid digestion and absorption:

  • Water-insoluble lipids are emulsified by bile acids for enzymatic digestion
  • TAGs are digested by pancreatic lipase to free fatty acids, mono- and diacylglycerol
  • Phospholipids are digested by pancreatic phospholipases
  • Cholesterol esters are digested by pancreatic cholesteryl ester hydrolase to free cholesterol
  • Absorption occurs in the form of mixed micelles by enterocytes, leading to the formation of chylomicrons
• Overview of lipid transport:

  • Lipids are transported in lipoprotein complexes
  • Major carriers of triglycerides are chylomicrons and VLDL
  • Remnants of chylomicrons are taken up by the liver
  • LDL delivers cholesterol from the liver to cells
  • HDL collects excess cholesterol from cells for reverse cholesterol transport
• Effect of diet on LDL concentrations:

  • Increase LDL: Saturated fatty acids, trans fatty acids, high cholesterol intake
  • Decrease LDL: High polyunsaturated fatty acid (PUFA) diet, omega-3 fatty acids, dietary fiber
• Hyperlipoproteinemia/dyslipoproteinemia:

  • Hypercholesterolemia: Increased total cholesterol, LDL, decreased HDL, a risk factor for atherosclerosis
  • Hypertriglyceridemia: Increased isolated triglycerides, risk of acute pancreatitis
  • Atherogenic particles like LDL, especially small dense LDL, are highly atherogenic and contribute to the risk of atherosclerosis
• Atherogenic particles:

  • LDL, especially small dense LDL, are the most atherogenic particles
  • LDL stays in plasma 9 times longer than VLDL
  • Risk of atherosclerosis rises with LDL concentrations
• Low HDL levels increase the risk of atherosclerosis even when total cholesterol and LDL levels are within the reference interval
• LDL carries approximately 70% of all cholesterol and is a major determinant of its plasma concentration
• The risk of atherosclerosis increases with LDL concentrations, but for any given LDL level, the risk is determined by HDL levels
• Atherogenic lipid profile includes:

  • Increased LDL, especially small, dense, oxidized particles
  • Increased apoB, which reflects LDL particle number better than the concentration of LDL
  • Decreased HDL
  • Increased apo(a)
  • Increased TAG if accompanied by increased FFA
• Normal lipid profile for patients:

  • Total cholesterol: <200 mg/dl or <5.18 mmol/l
  • HDL-C: >35 mg/dl or >0.90 mmol/l
  • LDL-C: <130 mg/dl or <3.36 mmol/l
  • TAG: <200 mg/dl or <2.83 mmol/l
• Primary disorders of lipid metabolism are not due to identifiable underlying diseases, while secondary disorders manifest as a result of other diseases
• Familial Hypercholesterolemia (FH) is highly related to heart disease and can be homozygous (type IIa) or heterozygous (type IIb)
• FH is caused by mutations in the LDLR gene on chromosome 19, with consequences including multiple skin and tendon xanthomas, premature atherosclerosis, and increased risk of myocardial infarction
• Familial Combined Hyperlipoproteinemia presents as high blood cholesterol and triglyceride levels, or either one, and is associated with excessive production of LDL by the liver
• Familial Hyperalphalipoproteinemia is characterized by increased levels of HDL-cholesterol and apo A1, reducing the risk of coronary heart disease
• Hypolipoproteinemia includes categories like Hypobetalipoproteinemia and Abetalipoproteinemia, with the latter being very rare and associated with the inability to absorb fats and fat-soluble vitamins
• Atherosclerosis is the leading cause of death and disability in the developed world, with high plasma concentrations of LDL correlating with the risk
• Two mechanisms explain the pathophysiology of atherosclerosis: chronic endothelial injury and elevated lipids
• Risk factors for coronary artery disease include elevated lipid levels, hypertension, smoking, diabetes mellitus, obesity, lack of exercise, oxidative stress, inflammation, and homocysteine accumulation