Biochemistry Lipid Metabolism

Triglycerides; lipid droplets

__________ represent over 95% of dietary lipids and is used as storage molecules for fuel. They are also water insoluble and can be stored as unsolvated ______________.

soluble

Digestive enzymes are water (soluble/insoluble).

emulsified; lipoproteins

Because digestive enzymes are water soluble, ingested triglycerides must be _________ before they can be digested enzymatically in the intestine. Triglycerides must be carried in the blood by protein carriers called __________________.

coenzyme A

Breakdown of triglycerides for fuel must involved an "activator molecule"--_______________ to counteract the C-C- bond stability (β oxidation).

40; 30

Over ______% of our daily energy requirements are supplied by dietary triacylglycerols even though nutritional guidelines recommend less than _____%.

1. Fats consumed in the diet
2. Fats stored in cells as lipid droplets
3. Synthesis of fats by the liver

What are the 3 ways in which humans obtain fatty acid fuels?

Bile acids (salts)

--Synthesized from cholesterol in the liver, stored in the gallbladder, and released into the small intestine after ingestion of a fatty meal
--Emulsify lipids into micelles
--Amphipathic, detergent-like molecules
--Aid in lipid breakdown and the absorption of the digested product

mixed micelles

Bile salts solubilize fat globules by emulsifying them into _________________ of bile salts and triacylglycerols.

BILE SPOTS

What is responsible for solubilizing triacylglycerols?

pancreatic lipase

Micelles allow interaction with water-soluble ________________________ in the intestine.

pancreatic lipase

Converts triglycerides to monoglycerides, diglycerides, free fatty acids and glycerol

intestinal mucosa

Products produced from triglyceride breakdown diffuse into __________________.

triacylglycerols; chylomicrons

Once lipid products diffuse into intestinal mucosa, they are reconverted to _________________ and are packaged into ____________________.

apolipoproteins

Lipid-binding proteins in the blood that transport triglycerides, phospholipids, and cholesterol between organs

apolipoproteins

What combines with lipids to form lipoproteins?

lipoproteins

Globular micelle-like particles with a nonpolar core of hydrophobic lipids surrounded by hydrophillic protein side chains and polar lipid head groups (5 different classes)

Chylomicrons

--Largest type of lipoprotein and least dense
--Synthesized in epithelial cells of the small intestine and transported via lymphatic tissue into the blood stream

chylomicrons

What is the largest type of lipoprotein?

epithelial cells of small intestine

Where are chylomicrons synthesized?

Lymphatic tissue into the blood stream

How are chylomicrons transported?

dietary triglycerides

The bloodstream delivers chylomicrons throughout the body to transport _____________________ to various tissues.

binding sites on the endothelium of capillaries (skeletal muscle & adipose tissue)

Where do the chylomicrons adhere to once they reach the capillaries?

lipoprotein lipase

What does apolipoprotein (ApoC-II) on chylomicrons activate within adipose tissue, the heart, skeletal muscle, and mammary tissue?

Lipoprotein lipase

Hydrolyzes triglycerides for fatty acid release from the chylomicron

Re-enter circulation to be taken up by the liver

Once chylomicrons shrink and leave chylomicron remnants, where do the chylomicron remnants go from here?

lysosomes; hepatocytes

Remainder of cholesterol that is released after re-entering blood circulation is degraded by ________________ in the ______________.

muscle; adipose tissue; cholesterol

Chylomicrons deliver dietary triglycerides to ___________ & _______________ and deliver dietary ______________ to the liver.

Liver

Where are VLDLs synthesized?

triacylglycerols; apolipoproteins

When the diet contains more fatty acids that are needed for fuel, FAs are converted to _______________ in the liver and are packaged with ________________, which are then exported as VLDLs.

Cholesterol & cholesterol esters

Besides triacylglycerols, what 2 other components make up VLDLs?

muscle and adipose tissue

What is the target tissue of VLDLs?

ApoC-II

What activates lipoprotein lipase?

lipid droplets; energy

Free fatty acids released from VLDLs are either stored as ______________ in adipocytes or are oxidized for _______ in muscle cells.

VLDLs

Transports endogenous triglycerides and cholesterol
Degraded by lipoprotein lipase in the capillaries of adipose and muscle tissue

Lipoprotein lipase

--Major enzyme involved in the processing of chylomicrons and VLDL by hydrolysis of fatty acids from triglycerides
--Different functions in different tissues

Provides energy

What is the function of lipoprotein lipase in cardiac and skeletal muscle?

Stimulates triacylglycerol storage

What is the function of lipoprotein lipase in adipose tissue?

increase

After eating a meal, elevated insulin levels cause a/an (increase/decrease) of lipoprotein lipase (LPL) activity in adipose tissue, consequently promoting fuel storage as triacylglycerols.

increase

After food has been absorbed, a decrease in insulin levels causes a/an (increase, decrease) of LPL activity within muscle tissue, releasing fatty acids from VLDL for use as fuel.

IDL (intermediate density lipoprotein)

--Loss of triglycerides from VLDL (aka VLDL remenants)
--Half are removed from blood stream by the liver
--Other half serves as precursor to low-density lipoproteins (LDL)

LDL

--Taken up by extrahepatic tissues or liver
--Further removal of triacylglycerol from VLDL
--Rich in cholesterol and cholesterol esters

Extrahepatic tissues & liver

What is the target tissue of LDLs?

ApoB-100

What is the major apolipoprotein of LDL?

ApoB-100

Binds lipoprotein to LDL receptors of target tissues

cholesterol; apoB-100

LDLs carry ___________ to specific tissues with _________ receptors.

Liver & small intestine

Synthesis location of HDL

Triglycerides

What is the primary composition of VLDLs?

skeletal muscle & adipose tissue

What are the target tissues of chylomicrons?

triglycerides

What makes up the primary composition of chylomicrons?

blood stream (from VLDL)

Where are IDLs synthesized?

Back to liver or converted to LDL

What is the target tissue of IDLs?

Triglycerides > cholesterol

What is the primary composition of IDLs?

Blood stream (from IDL)

Where are LDLs synthesized?

LDL receptors on target cells or the liver

What is the target of LDLs?

cholesterol

What is the primary composition of LDL?

Liver and small intestine

Where are HDLs synthesized?

Matures as it picks up cholesterol from tissues then carries it to liver for disposal

What is the primary destination for HDL?

Apolipoproteins (immature), cholesterol (mature)

What is the primary composition of HDL?

High-density lipoprotein (HDL)

--Small, protein-rich particles containing apolipoproteins, small amounts of cholesterol and LCAT enzyme

lecithin-cholesterol acyl transferase (LCAT)

--Catalyzes the formation of cholesterol esters

HDL

What lipoprotein is considered to be good cholesterol?

HDL

What lipoprotein extracts lipids (cholesterol) from chylomicrons and VLDL remnants?

Reverse cholesterol transport

HDL can pick up cholesterol in the tissues and carry it in the liver in this process (plaque reduction)

receptors

HDL particles acquire cholesterol by extracting it from cell-surface membrane ____________.

cholesteryl esters

Cholesterol is converted to _________________ by the HDL-associated enzyme, LCAT.

liver

What organ is the only organ capable of disposing of significant amounts of cholesterol?

SR-B1

What receptor of the liver selectively transfers HDL cholesterol into the liver?

Acyl-CoA: cholesterol acyltransferase (ACAT)

--Esterifies free cholesterol by linking it to a fatty acid
--Prepares cholesterol for storage in the liver cells
--Prepares cholesterol for packaging into chylomicrons/lipoproteins

ACAT

What prepares cholesterol for packaging into lipoproteins/chylomicrons?

LDL

Endogenous cholesterol produced in liver is distributed to peripheral tissues via ______.

LDL

What lipoprotein correlates positively with incidence of atherosclerotic heart disease?

cholesterol; down regulates

Number of LDL receptors depends on the accumulation of intracellular ________________. High concentrations of cholesterol intracellularly (up regulates/down regulates) transcription of the LDL receptor gene.

LDL receptor

The intracellular concentration of free cholesterol controls the rate of _________________ synthesis.

Receptor-mediated endocytosis

--Meets cellular requirements for cholesterol
--Prevents over-accumulation by inhibiting cholesterol synthesis

Nonspecific endocytic process

--"bulk phase pinocytosis"
--Plays no role in regulation of cholesterol and leads to excessive accumulation
--May result in atherosclerosis

β oxidation

Series of enzyme-catalyzed reactions that operates in a repetitive fashion to degrade fatty acids by progressively removing two-carbon units from the carboxyl ends (occurs in mitochondrial matrix)

Mitochondrial matrix

Where does β oxidation occur within the cell?

Fatty acyl-CoA synthase

Converts free fatty acids to high-energy compounds (fatty acyl-CoA)

cytoplasm; ATP

In β oxidation, where are free fatty acids first activated? Does this process require ATP?

Carnitine shuttle

Transports fatty acid chains (>12 carbons) to matrix from intermembrane space

1. Esterification to Coenzyme A
2. Transfer to carnitine followed by transport
3. Regeneration back to fatty acyl-CoA

What are the three steps of β oxidation?

exergonic; metabolic energy

The β oxidation pathway is highly (endergonic/exergonic) and functions to generate _______________________ through the breakdown of fatty acids.

fatty acyl-CoA; 2

Each round of β-oxidation requires a high energy ____________ (___ ATP equivalents) and an additional coenzyme A.

1 NADH, 2 FADH2, 1 acetyl-CoA and 1 fatty acyl-CoA

What is produced in each round of β oxidation?

7 rounds; 7; 7; 8

How many rounds of β oxidation will palmitoyl-CoA (C16) have to go through? How many NADH does this produce? FADH2? Acetyl-CoA?

8; 24, 8

The oxidation of 8 acetyl-CoA in the oxidation of palmitoyl-CoA (C16) produces how many GTP? NADH? FADH2?

129 ATP

How many net ATP are produced from the β oxidation of palmitoyl-CoA (C16)?

Ketogenesis

Acetyl-CoA converted to acetoacetate or β -hydroxybutyrate (ketone bodies)

Ketone bodies

--Important metabolic fuels for many peripheral tissues (converted back to acetyl-CoA)--heart and skeletal muscle
--Important for the brain in conditions of starvation

Ketosis

Ketone bodies are produced much faster than they are metabolized (often during starvation or untreated diabetes)

ketoacidosis

Overproduction of ketones that accumulate in the blood and lower blood pH; characteristic of sweet smelling breath (acetone)

fatty acid biosynthesis

Occurs through the condensation of C2-units-the reverse of β oxidation; mainly in liver and adipose tissue; takes place in cytoplasm

cytoplasm

Where does fatty acid biosynthesis take place?

endergonic

Fatty acid biosynthesis is an (exergonic/endergonic) process.

Malonyl-CoA

Fatty acid biosynthesis requires the participation of what 3-carbon intermediate?

1; 2

How many ATP are required per round of fatty acid biosynthesis? NADH?

ATP & NADPH

What two components are input into fatty acid synthesis?

NADH & FADH2

During β oxidation, what two components are formed?

Ketogenesis

What is an alternate pathway for acetyl-CoA to enter if we cannot enter the TCA cycle?

Protein Kinase A

What enzyme is responsible for activating glucagon?