BMB402 Lipid Metabolism

Carnitine Transport Cycle

three-step process that translocates fatty acids across the inner mitochondrial membrane

β-oxidation pathway

A fatty acid oxidation pathway that removes two-carbon units from a fatty acid chain, producing FADH2, NADH, and acetyl-CoA

Ketone Bodies

Acetoacetate and D-β-hydroxybutyrate formed by ketogenesis in the liver and used elsewhere in the body to make acetyl-CoA

Citrate Shuttle

mechanism for transporting acetyl-CoA groups via citrate from mitochondria to the cytosol, where they are used for fatty acid synthesis

Sterol Regulatory Element Binding Protein (SREBP)

dimeric DNA-binding protein that binds to sterol regulatory elements and regulates gene expression

Lipoprotein

A molecular complex composed of a core of hydrophobic lipids surrounded by a shell of polar lipids and apolipoproteins

Chylomicron

Large lipoprotein particles that transport triacylglycerols from the intestines to tissues throughout the body

Bile Acid

Polar molecules derived from cholesterol that are secreted into the intestines where they emulsify dietary lipids, which aids in lipid absorption

β-oxidation purpose

provides energy to cells when glucose levels are low

FA synthesis purpose

Liver and adipose cells convert excess acetyl-CoA into fatty acids that can be stored or exported as triacylglycerols

β-oxidation net reaction

Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP -> 8 Acetyl-CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+

FA synthesis net reaction

: 8 Acetyl-CoA + 7 ATP + 14 NADPH + 14 H+ -> Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O

key enzymes for β-oxidation

fatty acyl-CoA synthetase, carnitine acyltransferase I (rate-limiting)

key enzymes for FA synthesis

acetyl-CoA carboxylase (rate-limiting), fatty acid synthase

key enzyme for cholesterol synthesis

HMG-CoA reductase, targeted by statins

β-oxidation location

mitochondrial matrix

FA synthesis location

cytosol

fatty acyl-CoA synthetase

catalyzes priming reaction, converts free fatty acids in cytosol to fatty-acyl CoA

carnitine acyltransferase I

catalyzes the rate-limiting step in fatty acid oxidation, links fatty acyl-CoA to carnitine so they can be transported across inner mitochondrial membrane

acetyl-CoA carboxylase

catalyzes the rate-limiting step in fatty acid synthesis by forming malonyl-CoA from acetyl-CoA

fatty acid synthase

catalyzes a series of reactions that adds 2 carbon units to the growing FA chain

HMG-CoA reductase

catalyzes the rate limiting step in the cholesterol biosynthesis, the NADPH-dependent reduction of HMG-CoA to mevalonic acid

when cell energy is low, how does carnitine transport cycle respond?

important fatty acyl-CoA into matrix for degradation

when cell energy is high, how does carnitine transport cycle respond?

FA synthesis is favored, malonyl-CoA inhibits flux into matrix to block degradation

Step 1 of β-oxidation

oxidation - forms FADH2 and makes a C=C bond

Step 2 of β-oxidation

hydration - adds H2O across the C=C bond made in Step 1

Step 3 of β-oxidation

oxidation - forms NADH

Step 4 of β-oxidation

thiolysis - removes a C2 unit from the FA chain and forms acetyl-CoA

necessary precursors for β-oxidation

CoA, FAD, NAD+, RLS = carnitine acyltransferase I

necessary precursors for FA synthesis

need acyl carrier protein (ACP), NADPH, RLS = acetyl-CoA carboxylase which makes malonyl-CoA

how many passes of β-oxidation are required to break down palmitic acid and how much acetyl-CoA and ATP are made?

7 passes and produces 106-108 ATP

regulators of FA biosynthesis and inhibitors

acetyl-CoA carboxylase, inhibited by palmitoyl-CoA and glucagon and epinephrine, activated by citrate and insulin

ketogenesis

production of ketone bodies (acetoacetate and D-β-hydroxybutyrate) in liver due to excess acetyl-CoA

conditions for ketogenesis

starvation, limited carbohydrates, ketone bodies become energy source for muscles and brain

statin effect on cholesterol synthesis

inhibits HMG-CoA reductase to block RLS of synthesis

cholesterol functions

stored in lipid droplets as cholesterol ester, packaged into lipoproteins and exported to tissues, secretes into small intestine via bile duct for emulsification

cholesterol synthesis regulation:

SREBPs - upregulated when intracellular cholesterol is low, bind to SRE sequences and active transcriptional control of cholesterol synthesis genes

elongation enzymes

used to increase carbon chain in palmitate to make longer FAs

desaturating enzymes

membrane-bound ER proteins that use O2 as an oxidizing agent to produce unsaturated fatty acids

stage 1 cholesterol synthesis

2 acetyl-CoA are condensed via HMG-CoA reductase to form mevalonate (C6)

rate limiting step of cholesterol synthesis

stage 1 - HMG-CoA reductase

stage 2 cholesterol synthesis

ATP donates 2 Pi, isoprene (C5) is used to make dimethylallyl diphosphate, releases CO2

stage 3 cholesterol synthesis

isoprene (C5) units are attached to form farnesyl diphosphate (C15) then squalene (C30) using NADPH from PPP

stage 4 cholesterol synthesis

squalene (C30) is cyclized, 19 steps later makes cholesterol (C27)

major functions of cholesterol

stored in intracellular lipid droplets, packaged into lipoproteins and exported thru bloodstream, secretes into small intestines thru bile duct

apolipoproteins

membrane-bound vesicles w/ hydrophobic core and 1+ proteins on surface

structure of lipoproteins

phospholipid monolayer with cholesterol and 1+ apolipoproteins

function of lipoproteins

signaling molecules, differ depending on protein:triglyceride ratio and density

examples of lipoproteins

chylomicrons, VLDL, IDL, LDLs

HDL function

uptake of lipids from periphery and transport to liver thru apoA-I

chylomicron function

package lipids from intestine and carry them in bloodstream to liver

function of fatty acids in membranes

can covalently bond to proteins to tether them to biological membranes

higher unsaturation = ____ melting point

lower due to lower IMFs

hydrogenation

increases saturation of lipids, raises MP, easier to transport/longer shelf life, semisolid

result of partial hydrogenation

production of trans fats which cause high rates of CVD (high LDL, low HDL)

is HDL good or bad

good

is LDL good or bad

bad

LDL function

bring lipids from liver to periphery

waxes

long chain alcohols linked to long-chain fatty acids, high melting point

where are triacylglycerols packaged and where are these assembled?

VLDL particles assembled in ER and golgi

lipid droplets

storage vehicle for triacylglycerol in adipocytes surrounded by phospholipid monolayer

triacylglycerol metabolism

cleaved by lipases to generate free FAs and glycerol, pass thru lumen of intestinal epithelial cells

effect of glucagon on lipid signaling

activates FA release into bloodstream using GPCR

what transport molecule transports free fatty acids?

albumin

types of lipids in cell membrane

glycerophospholipids, sphingolipids, cholesterol

what enzyme releases signaling molecules from glycerophospholipids

phospholipase

sphingolipid general structure

sphingosine and one fatty acid

Tay-Sachs disease

defective hexosaminidase A causes a building up GM2 ganglioside (sphingolipid) in spleen and brain - developmental delays and death

lipid raft

area of membrane with large transmembrane proteins and packed with cholesterol, act as receptors for extracellular signaling

what is the precursor to steroid hormones and bile acids

cholesterol

steroid hormones

ligands for nuclear receptor proteins which mediate hormone signals by altering the expression for specific genes, critical for development and reproduction

synthetic hormones

agonists that mimic biological response of hormone

vitamin D

sunshine vitamin, derived from cholesterol cia UV light, need 10 mins outdoors

eicosanoids

signaling molecules derived from C20 polyunsaturated fatty acids that play a role in inflammation

release and modification of eicosanoids

released from membrane by phospholipases and modified by mitochondrial enzymes

signaling initiated by eicosanoids

paracrine

NSAIDs general mechanism

inhibit enzymes that produce inflammatory lipids to decrease inflammation

COX-1

broadly expressed inflammatory enzyme, produces molecules that stimulate mucin to protect stomach from decreasing pH

COX-2

inflammatory enzyme that doesn't affect GI health

nonselective COX-1/-2 inhibitors

broadly inhibit COX-1 and COX-2, used to treat inflammation, swelling, pain and fever

selective COX-2 inhibitors

inhibits COX-2, increases platelet aggregation, less GI problems