Lipogenesis & Cholesterol metabolism (Lect. 7)

Vocabulary flashcards covering lipogenesis, cholesterol metabolism, ketone bodies, fatty acid oxidation, lipoproteins, lipid digestion/absorption, glycogen and gluconeogenesis, PPP, amino acid metabolism, ammonia/urea cycle, and related regulatory pathways as presented in PHB114 notes.

Lipogenesis

Biosynthesis of triacylglycerol (TAG) from excess carbohydrates and protein; comprises fatty acid synthesis, glycerol-3-phosphate formation, and TAG assembly.

TAG (Triacylglycerol)

Main storage form of fatty acids, stored primarily in adipose tissue.

De novo fatty acid synthesis

Cytoplasmic synthesis of fatty acids from acetyl-CoA via the fatty acid synthase (FAS) system.

ACC (Acetyl-CoA carboxylase)

Rate-limiting enzyme that carboxylates acetyl-CoA to malonyl-CoA; activated by insulin, inhibited by glucagon/epinephrine; citrate stimulates.

FAS (Fatty acid synthase)

Multienzyme complex that performs successive condensation of acetyl/malonyl units to produce palmitate (C16:0); contains MAT, KS, KR, HD, ER, TE and ACP.

Malonyl-CoA

Two-carbon donor formed from acetyl-CoA by ACC; committed substrate for fatty acid elongation.

ACP (Acyl carrier protein)

Small protein with pantothenic acid that carries growing fatty acyl chains during fatty acid synthesis; contains a reactive SH group.

MAT (Malonyl transferase)

Enzyme in FAS that transfers acetyl/malonyl groups to ACP during fatty acid synthesis.

KS (β-ketoacyl synthase)

Enzyme in FAS that condenses acetyl-ACP with malonyl-ACP to extend the fatty acid chain.

KR (β-ketoacyl reductase)

Enzyme in FAS that reduces β-ketoacyl-ACP during chain elongation.

HD (β-hydroxyacyl dehydratase)

Enzyme in FAS that dehydrates β-hydroxyacyl-ACP to form enoyl-ACP.

ER (Enoyl reductase)

Enzyme in FAS that reduces enoyl-ACP to a saturated acyl-ACP.

TE (Thioesterase)

Enzyme in FAS that releases the finished fatty acid from ACP (often palmitate).

Acyl carrier protein (ACP)

Carrier protein within FAS carrying growing acyl chains via its SH group.

Palmitic acid

End-product of de novo fatty acid synthesis in most tissues (C16:0).

Citrate shuttle

Mechanism moving acetyl-CoA from mitochondria to cytosol by exporting citrate and regenerating acetyl-CoA in the cytosol.

NADPH sources for FA synthesis

NADPH is supplied by the pentose phosphate pathway, cytosolic isocitrate dehydrogenase, and the malic enzyme.

Location of de novo FA synthesis

Occurs in liver, adipose tissue, and lactating mammary gland.

Carboxylation of acetyl-CoA (ACC reaction)

Acetyl-CoA is carboxylated to malonyl-CoA by acetyl-CoA carboxylase (biotin & ATP); rate-limiting step.

Mevalonate pathway

Pathway for cholesterol synthesis beginning with acetyl-CoA leading to mevalonate and ultimately cholesterol.

HMG-CoA synthase

Enzyme that forms HMG-CoA from acetyl-CoA and acetoacetyl-CoA during cholesterol synthesis.

HMG-CoA reductase

Key rate-limiting enzyme that reduces HMG-CoA to mevalonate; active form is dephosphorylated.

Mevalonate

Mevalonate is a central intermediate destined to become cholesterol in the mevalonate pathway.

Regulation of HMG-CoA reductase

Controlled by cholesterol feedback, hormones (glucagon inhibits, insulin stimulates), and statin drugs (e.g., mevastatin, lovastatin) inhibit the enzyme.

Functions of cholesterol

Structural component of cell membranes; precursor for steroid hormones, bile acids, and vitamin D3.

Plasma cholesterol forms

Cholesterol in plasma exists as free cholesterol and cholesterol esters; total cholesterol typical range 140–220 mg/dL.

Hypercholesterolemia

Elevated plasma cholesterol (>220 mg/dL); causes include diet, diabetes, obesity, hypothyroidism, liver disease, familial hypercholesterolemia.

Lipoproteins

Lipid-protein particles that transport lipids in blood: chylomicrons, VLDL, LDL, HDL with various apolipoproteins.

Chylomicrons

Intestinal lipoproteins carrying dietary TG from intestine to tissues; contain apo B-48; acquire apo CII and apo E from HDL.

VLDL

Liver-derived lipoprotein transporting TG from liver to tissues; contains apo B-100; acquires apo CII and apo E from HDL.

LDL

Low-density lipoprotein delivering cholesterol to peripheral tissues; high cholesterol load suppresses LDL receptor expression; contains apo B-100.

HDL

High-density lipoprotein involved in reverse cholesterol transport; contains apo A1, apo CII, and apo E; activates LCAT; picks up cholesterol from tissues.

LCAT

Lecithin-cholesterol acyltransferase; plasma enzyme that esterifies cholesterol on HDL to cholesteryl esters, aiding reverse transport.

Lipoprotein lipase (LPL)

Enzyme on capillary endothelium that hydrolyzes TG in chylomicrons and VLDL to glycerol and fatty acids.

Absorption of lipids

Digestion by pancreatic lipase to monoacylglycerol (MAG) and free fatty acids; bile salts form micelles; chylomicrons form in enterocytes with apo B-48.

Steatorrhea

Fat in stool due to defective digestion/absorption (pancreatic lipase deficiency, bile duct obstruction, mucosal disease).

Chyluria

Presence of chylomicrons (fat) in urine after a fatty meal due to lymphatic-urinary tract connection.

Fatty liver (steatosis)

Accumulation of fat in the liver; causes include excess fat influx, impaired export, or reduced fatty acid oxidation; can progress to fibrosis.

Lipolysis

Hydrolysis of TAG in adipose tissue to glycerol and free fatty acids; key enzyme is hormone-sensitive lipase (HSL).

Hormone-sensitive lipase (HSL)

Rate-controlling enzyme of lipolysis; activity depends on phosphorylation state (activated when phosphorylated).

Glycerol-3-phosphate

Backbone for TAG; formed from DHAP in adipose tissue or glycerol kinase in liver; used for TAG synthesis.

Glycogenogenesis (glycogenesis)

Formation of glycogen from UDP-glucose; glycogenin primer; glycogen synthase extends chains; branching enzyme creates α1-6 branches.

Glycogenolysis

Breakdown of glycogen by glycogen phosphorylase, transferase, and debranching enzyme.

Gluconeogenesis

Formation of glucose from non-carbohydrate sources (lactate, pyruvate, glycerol, some amino acids); mainly in liver; bypasses three irreversible glycolysis steps via pyruvate carboxylase, PEP carboxykinase, and fructose-1,6-bisphosphatase; involves malate shuttle to convert oxaloacetate for cytosolic gluconeogenesis.

Pyruvate dehydrogenase (PDH) complex

Mitochondrial enzyme complex that converts pyruvate to acetyl-CoA; requires TPP, lipoic acid, CoA-SH, FAD, and NAD; yields NADH.

TCA cycle energy yield

Per turn, 3 NADH, 1 FADH2, and 1 GTP (ATP) are produced, totaling about 12 ATP when coupled to oxidative phosphorylation.

NADH shuttles

Mechanisms to transfer cytosolic NADH energy into mitochondria: glycerol-3-phosphate shuttle (4 ATP) and malate-aspartate shuttle (6 ATP).

Glycolysis irreversible enzymes

Hexokinase (or glucokinase in liver), phosphofructokinase-1 (PFK-1), and pyruvate kinase; regulation integrates hormonal signals.

Cori cycle

Cycle where lactate produced by anaerobic glycolysis in muscle is transported to liver and converted to glucose via gluconeogenesis.

Glycolysis intermediates utility

Important intermediates: DHAP for glycerol-3-phosphate (lipogenesis); 3-phosphoglycerate for serine; pyruvate for alanine; pyruvate converted to acetyl-CoA in mitochondria (aerobic glycolysis).

RBC glycolysis importance

RBCs lack mitochondria; rely on glycolysis for ATP; lactate is the end product; glucose uptake is insulin-independent.

PPP (Pentose phosphate pathway)

Minor pathway for glucose oxidation producing NADPH and ribose-5-phosphate; oxidative phase yields NADPH; non-oxidative phase interconverts sugars.

G6PDH

Glucose-6-phosphate dehydrogenase; rate-limiting enzyme of the oxidative phase of PPP; stimulated by insulin and NADP+, inhibited by NADPH.

Glycine functions

Non-essential amino acid; heme synthesis (via ALA), hippuric acid formation, glutathione synthesis, bile acid conjugation, nucleotide synthesis, creatine production.

Phenylalanine & tyrosine metabolism

Phenylalanine is essential; converted to tyrosine by phenylalanine hydroxylase; PKU results from enzyme deficiency; Tyrosine is ketogenic and glucogenic and becomes essential if phenylalanine hydroxylase is deficient.

Albinism

Inborn deficiency in tyrosine metabolism (tyrosinase) causing lack of melanin.

Alkaptonuria

Deficiency of homogentisate oxidase; accumulation of homogentisic acid (ochronosis) with dark urine and connective tissue pigmentation.

Urea cycle (ornithine cycle)

Liver pathway converting toxic ammonia to urea for excretion; steps include CPS-1 forming carbamoyl phosphate, ornithine transcarbamoylase, argininosuccinate synthase, argininosuccinate lyase, and arginase; regulated by N-acetylglutamate (NAG).

Ammonia toxicity

Hyperammonemia causing CNS effects; processed via excretion, glutamine synthesis, and urea cycle; severe levels can cause coma.

Gluconeogenesis shuttle (malate/oxaloacetate)

Transport of oxaloacetate from mitochondria to cytosol as malate for gluconeogenesis when oxaloacetate cannot cross the mitochondrial membrane.

Lipid digestion & absorption

Pancreatic and lingual/gastric lipases degrade TAG to MAG and FFA; bile salts form micelles; enterocytes re-esterify to TG and assemble chylomicrons with apo B-48.

Steatorrhea & chyluria

Steatorrhea: fat in stool due to digestion/absorption problems; Chyluria: fat in urine due to lymphatic-urinary tract communication.

Glycerol and lipid fate after absorption

Glycerol and FFAs can be used for adipose storage (TAG), oxidation for energy, or gluconeogenesis (glycerol) depending on tissue and energy status.

Lipid oxidation energy yield (palmitic acid)

Beta-oxidation of palmitic acid yields up to about 129 ATP per molecule when fully oxidized including activation cost and shuttle contributions.

Propionic acid metabolism (odd-chain FA)

Odd-chain fatty acids yield propionyl-CoA, which is converted to succinyl-CoA and enters the TCA cycle.