IMPAIRED MEMBRANE HOMEOVISCOSITY IN DISEASES WHICH ACCOMPANY ECOMOMIC DEVELOPMENT AND ARE CHARACTERIZED BY DYSLIPIDEMIA, CELLULAR HYPOXIA, OXIDATIVE STRESS, INFLAMMATION, AND AUTOIMMUNITY NANCY HART Peace Health Saint Joseph Medical Center, Bellingham, WA, USA,
[email protected], 01-360-393-4380
OBJECTIVE: Economic development generates a diet with increased levels of trans and long-chain saturated fatty acids and a high omega-6 to 3 fatty acid ratio, as well as increased incidences of cardiovascular, autoimmune, and degenerative diseases. These "diseases of development" are characterized by dyslipidemia, cellular hypoxia, inflammation, oxidative stress, and autoimmunity. This presentation offers a cell membrane-based model of how variations in dietary lipids might impact membrane viscosity and the environment of intrinsic membrane proteins and give rise to these pathological elements.
METHODS: Literature review.
RESULTS: Phospholipid membranes function optimally at a specific viscosity that is maintained by a balance of membrane stiffening trans and long-chain saturated acyl groups with polyunsaturated fatty acids, which increase membrane flexibility1. Because most acyl chains are incorporated into cell membranes unchanged from the form in which they were absorbed from the gastrointestinal tract, diet is a major determinant of cell membrane viscosity.
DIETARY LIPIDS
DIETARY LIPIDS ALTER MEMBRANE FLEXIBILITY
Optimal Viscosity
Optimal Viscosity
Optimal Diet
Modern Diet
High monounsaturates and medium-chain saturated fatty acids maintain cell membranes close to optimal viscosity.
High trans fatty acids and long chain saturates require large amounts of polyunsaturates and cholesterol to maintain optimal cell membrane viscosity.
Fatty Acids
Stiffen Membranes
Increase Flexibility
Moderate Viscosity
Omega - 6 Omega - 9 Omega - 3
Monounsaturates Medium Chain Saturates Cholesteral
Trans fat Long Chain Saturates
• • • •
Trans Fatty Acids < 1% dietary fat Low in long-chain saturated fatty acids Omega 6 to 3 fatty acid ratio < 6:1 Large % medium-chain saturated & monounsaturated fatty acids 2
1
Modern Diet
Optimal Diet
Sinensky M. Homeoviscous adaptation- a homeostatic process that regulates the viscosity of membrane lipids in Escherichia coli. Proc Natl Acad Sci USA 1974; 71: 522–525.
• • • •
Trans Fatty Acids up to 30% of dietary fat High in long-chain saturated fatty acids Omega 6 to 3 fatty acid ratio up to 56:1 Smaller % medium-chain saturated & monounsaturated fatty acids
Simopoulos AP, Cleland LG (eds): Omega - 6 / Omega -3 Essential Fatty Acid Ratio: The Scientific Evidence. World Rev Nutr Diet, Basel, Karger, 2003; 92, 1-22.
CONCLUSION Therefore, dietary changes accompanying economic development may be fundamental in the etiologies of a broad range of idiopathic diseases including essential hypertension, autoimmune disorders, and Alzheimer’s disease. Metabolic Autoimmune Alzheimer’s Autism COPD Hypertension Preeclampsia Syndrome Schizophrenia Diseases Disease Dyslipidemia
Dyslipidemia
Cellular Hypoxia
Cellular Hypoxia
Oxidative Stress
Oxidative Stress
Autoimmunity
Autoimmunity
HYPOXIA
AUTOIMMUNITY
OXIDATIVE STRESS
Stiff cell membranes slow transmembrane oxygen transport3, and might increase hypoxia inducible factor, which serves as the maun regulator of gene transcription in response to cellular hypoxia4.
A change in the membrane lipid environment might alter integral membrane proteins5 in a way that disrupts cell membrane signaling and leads to autoimmunity.
Stiff mitochondrial membranes might alter the function of electron transport proteins and cause an increase in oxidative stress.
Optimal Endothelial Stiffness: No Autoimmunity
Mitochondrial Membranes of Optimal Stiffness: Low Oxidative Stress
•
Optimal Membrane Viscosity: No Cellular Hypoxia
•
Hypothetical intrinsic membrane protein with amino acid sequence “A - B - C - D - E - F - G - H - I - I - J - K - L - M ” “B - C - D - E ” is exposed to intravascular space and is recognozed by the immune system as native protein, therefore: No antibodies
Mitochondrial proteins are in native conformation so electrons are passed from one redox center to the next without shortcuts and oxidative stress is low.
Stiff Endothelium: Autoimmunity
Stiff Membranes: Cellular Hypoxia
• •
Hypothetical intrinsic membrane protein with amino acid sequence “A - B - C - D - E - F - G - H - I - I - J - K - L - M ” “F - H - I - J ” is exposed to the intravascular space and is recognozed by the immune system as foreign, therefore: Auto antibodies formed
Mitochondria with Stiff Membranes: Oxidative Stress
Stiff membranes might distort mitochondrial membrane proteins causing a change in the electron affinity of the redox center. Electrons escape causing oxidative stress. 3
Fischkoff S, Vanderkooi JM. Oxygen diffusion in biological and artificial membranes determined by the fluorochrome pyrene. J Gen Physiol 1975; 65(5): 663-676. 5 4
Maxwell PH. Hypoxia-inducible factor as a physiological regulator. Exp Physiol 2005; 90: 791-797.
Niu SL, Mitchell DC, Litman BJ. Trans fatty acid derived phospholipids show increased membrane cholesterol and reduced receptor activation as compared to their cis analogs. Biochemistry 2005; 44(11): 4458-4465.
