Metabolic: lecture 26

Lipid Metabolism

• One-third of energy needs come from dietary triacylglycerols (TAGs).
• Fatty acid oxidation is a major energy source.
• About 80% of mammalian heart and liver energy needs are met by fatty acid oxidation.

Hibernating Animals and Polar Bears

• These animals obtain most energy from stored fatty acids.

Fats Provide Efficient Fuel Storage

• Fatty acids carry more energy per carbon because they are more reduced.
• Fatty acids can be packed more efficiently because they are nonpolar.
• Glucose and glycogen provide short-term, fast-delivery energy needs.
• Fats provide long-term (months) energy storage and slow delivery.

Mobilization of Fats

• Dietary fats provide quick delivery.
• Storage fats provide slower delivery.
• Dietary fatty acids are packaged into chylomicrons.
• Fatty acids are released and absorbed in the small intestine.
• Emulsification of fats occurs in the small intestine, breaking down TAGs to monoglycerides and free fatty acids.
• These smaller molecules are taken up by the intestinal mucosa, converted to triacylglycerols, and packaged into chylomicrons.
• Chylomicrons facilitate transport through lymphatic and bloodstream.
• Within the intestinal mucosa, broken-down lipids reassemble into TAGs. Bile salts emulsify dietary fats.
• Fatty acids are hydrophilic/lipophilic, requiring emulsification to avoid flushing out of the body.

Lipids Are Transported in the Blood

• Lipids are hydrophobic and need packaging with apolipoproteins for transport.

Application: Avoiding Hepatic Metabolism During Drug Delivery

• Small lipophilic drugs associated with long-chain triglycerides can be incorporated into chylomicrons and taken from the intestines to the lymph to the bloodstream, thus avoiding the liver.
• MCT = medium chain triglycerides
• GML = glyceryl monolinoleate, a long-chain triglyceride
• SEDDS = a self-emulsifying formula made with GML

Types of Lipoproteins

• Chylomicrons: largest
• VLDL: very low-density lipoprotein
• IDL: intermediate-density lipoprotein
• LDL: low-density lipoprotein
• HDL: high-density lipoprotein

Lipases Cleave Fatty Acids from Glycerol Backbone of TAGs

• Lipases cleave fatty acids from glycerol backbones of triacylglycerides (TAGs) to give glycerol + 3 fatty acids.

Hormones Trigger Mobilization of Stored Triacylglycerols

• Glucagon and epinephrine bind to receptors in adipocyte membranes.
• Adenylyl cyclase is stimulated, producing cAMP.
• cAMP activates protein kinase A (PKA).
• PKA phosphorylates hormone-sensitive lipase (HSL).
• Perilipin molecules on lipid droplets dissociate from CGI, activating adipose triacylglycerol lipase (ATGL).
• Released fatty acids enter the bloodstream.

Glycerol from Fat Enters Glycolysis

• Glycerol kinase phosphorylates glycerol, using ATP.
• Subsequent oxidation of glycerol 3-phosphate recovers more ATP—cost-covered.
• This allows for limited anaerobic catabolism of fats.

Fatty Acids Must Be Transported into Mitochondria for Oxidation

• Fats are degraded to fatty acids and glycerol in adipocytes.
• Fatty acids are transported to tissues via blood.
• Small (<12 carbons) fatty acids diffuse freely across mitochondrial membranes.
• Larger fatty acids use acyl-carnitine/carnitine transporter for transport into mitochondria.

Intracellular Transport Requires Conversion to Fatty Acyl-CoA

• Fatty acids are converted to fatty acyl-CoA using CoA synthetase, ATP, and CoASH.
• This reaction is very favorable.

Acyl-Carnitine/Carnitine Transporter

• Acyl-carnitine/carnitine transporter facilitates transport of fatty acyl carnitine into the mitochondrial matrix.
• A counter-exchange with carnitine occurs.

Fatty Acid Oxidation Occurs in the Mitochondria in Three Stages

• Stage 1: oxidative conversion of 2-carbon units from fatty acids to acetyl-CoA via β-oxidation, generating NADH and FADH₂.
• Stage 2: oxidation of acetyl-CoA into CO₂ via the citric acid cycle, generating NADH and FADH₂.
• Stage 3: ATP production from NADH and FADH₂ via oxidative phosphorylation.

The β-Oxidation Pathway

• Each pass of β-oxidation removes one acetyl-CoA molecule.
• Oxidation (FAD), hydration, oxidation (NAD), and thiolation reactions yield acetyl-CoA, regenerating FAD and NAD.

Oxidation of Unsaturated Fatty Acids

• Oxidation yields one fewer FADH₂ molecule during isomerization but generates 1 FADH₂ during the first step of the next cycle.
• NADPH reduces the remaining unsaturated bond.

NADH and FADH₂ Yield of ATP

• NADH and FADH₂ generated during fatty acid oxidation serve as sources for ATP production.
• These values assume 2.5 ATP per NADH and 1.5 ATP per FADH₂ during oxidative phosphorylation.

Hydration Step 2: Enoyl-CoA Hydratase

• Two isoforms: soluble short-chain (crotonase) and membrane-bound long-chain hydratase.
• Water adds across the double bond, producing alcohol on β-carbon.
• Analogous to a fumarase reaction in the citric acid cycle.

Oxidation Step 3: β-hydroxyacyl-CoA dehydrogenase

• Uses NAD as the hydride acceptor.
• Analogous to malate dehydrogenase in the citric acid cycle.

Oxidation Step 4: Acyl-CoA acetyltransferase (thiolase)

• CoA-SH picks up the fatty acid chain.
• Net reaction = thiolysis of carbon-carbon bond, producing acetyl-CoA.

This quiz delves into the critical aspects of lipid metabolism, focusing on how fats serve as an energy source for various animals, particularly hibernating species like polar bears. It covers the mobilization of dietary fats, energy efficiency of fatty acids, and the comparison between short-term and long-term energy storage mechanisms.