Cholesterol_Biosynthesis_FA23 (1).pptx

CHOLESTEROL BIOSYNTHESIS Vanessa De La Rosa, PhD CV I SESSION OBJECTIVES •Describe sterol synthesis from acetyl-CoA to cholesterol, including key enzymes, intermediates and rate limiting steps. •Explain the transcriptional, hormonal and post translational mechanisms that regulate cholesterol bios...

CHOLESTEROL BIOSYNTHESIS Vanessa De La Rosa, PhD CV I SESSION OBJECTIVES •Describe sterol synthesis from acetyl-CoA to cholesterol, including key enzymes, intermediates and rate limiting steps. •Explain the transcriptional, hormonal and post translational mechanisms that regulate cholesterol biosynthesis. •Identify key sterols derived from cholesterol and pharmacological targets of cholesterol synthesis. •Describe genetic deficiencies in cholesterol synthesis, such as Smith-Lemli-Opitz syndrome. •Compare and contrast the structure and function of cholesterol and cholesterol esters •Predict the effect of plasma cholesterol levels on the intracellular synthesis of cholesterol and the transcriptional regulation of cholesterol responsive genes 2 OVERVIEW OF CHOLESTEROL •Cholesterol synthesis is important for producing precursors to many metabolic processes •Making cholesterol de novo is energetically expensive •Liver is the major site of cholesterol synthesis •Important in the etiology of atherosclerosis FUNCTIONS OF CHOLESTEROL • essential constituent of plasma & intracellular membranes • regulates fluidity of lipid bilayer • lateral mobility of macromolecules & proteins Abundant (~20%) component of the myelin sheath (insulates axons of neurons & facilitates the conductance of an action potential). 4 CHOLESTEROL SYNTHESIS OVERVIEW •De novo synthesis encompasses 37 steps •Sterols (and other polyisoprenoids) differ from other types of complex lipids •Derived from 5-carbon isoprene units rather than fatty acids OVERVIEW OF REGULATION Liver is major site of biosynthesis Cytoplasm Nucleus ↓ HMG-CoA reductase expression ↓ De novo synthesis Statins inhibit HMGCoA reductase ↓ cholesterol ↓ intermediates (isoprenoid precursors) for other biomolecules Rate limiting step!! Sterolmediated transcripti on Steroid hormones Bile salts Vitamin D CHOLESTEROL SYNTHESIS: STAGE 1 Rate limiting step! • Cytosolic HMG-CoA synthase first enzymatic reaction • HMG-CoA reductase is rate limiting step (located in ER) • Cytosolic pool of acetyl-CoA required for cholesterol synthesis • NADPH provides reducing equivalents • Acetyl CoA must be transported from mitochondria to cytoplasm 8 STAGE 2: ACTIVATED ISOPRENES •2 major isoprenes formed •Large ATP requirement •Isoprenes used in the synthesis of coenzyme Q 9 FINAL STEPS OF CHOLESTEROL SYNTHESIS Stage 3 Stage 4 squalene converted to cholesterol in 13 reactions! CHOLESTEROL BIOSYNTHESIS REGULATION A. Conformation change and translocation Cleavag e Transcriptional regulation via SREBP2 B. Self-regulation C. Hormonal regulation Phosphorylat ion inactivates CHOLESTEROL FATE •Majority of cholesterol is stored as cholesterol ester •ACAT transfers fatty acid to hydroxyl group •Bile acids •Steroid hormonesFuture sessions •Vitamin D SMITH LEMLI OPITZ SYNDROME (SLOS) •Most common disorder of sterol synthesis •7-dehydrocholesterol reductase deficiency 7dehydrocholester ol Clinical Note Syndactyly of the second and third toes is the most frequently reported clinical finding 7-dehydrocholesterol reductase Vitamin D • variable clinical presentations • severe: affected infants have multiple congenital anomalies (craniofacial & limb) and severe neurological impairment • mild: learning and autistic-like behavioral problems with minor physical abnormalities