Lipid Metabolism Review

Lipid Metabolism Study Notes

Overview of Lipid Metabolism

  • Lipid metabolism encompasses several key processes including lipid synthesis, lipolysis, β-oxidation, and ketogenesis.

    • Study includes understanding the delivery of fatty acids to tissues, storage forms, hormonal and enzymatic involvement, metabolic states, and locations where pathways operate.

Key Questions in Lipid Metabolism

  • What happens post-delivery of fatty acids?

    • Storage forms and usage scenarios.

    • Hormones and enzymes involved.

    • Metabolic states impacting lipid metabolism.

    • Tissues and organelles where lipid metabolic pathways occur.

    • Different metabolic processes involved with lipid utilization.

Lipid Pathways

  • Lipid Synthesis (Post-prandial State)

    • Occurs mainly in:

    • Gut

    • Liver

    • Adipose Tissue

  • Lipolysis

    • Activated during:

    • Fasting

    • Exercise

    • Low-CHO Diets

    • Primary site: Adipose tissue in the body.

Constant Fatty Acid Cycling

  • Adipose tissue continuously takes up and releases fatty acids to meet energy needs despite sporadic eating patterns.

Postprandial Response of Plasma Triacylglycerol (TAG)

  • Measurement: In response to a moderate meal (1/3 daily calorie intake), plasma triacylglycerol levels shift over time post-meal.

  • Response Index:

    • 0 hrs: 0%

    • 3 hrs: 40%

    • 6 hrs: 60%

    • 12 hrs: 80%

Fuel Availability and Hormone Levels After Eating

  • Timeline: Shifts from Postprandial/Fed/Absorptive to Postabsorptive, then to Fasting and finally Starvation.

  • Key factors include Blood ketones, Blood fatty acids, Liver glycogen, Glucagon, Insulin, and Blood glucose levels.

Non-Esterified Fatty Acids (NEFA) in Blood Concentrations

  • FFA Levels: Vary under different states:

    • Fed: 0.3-0.6 mM

    • Starvation: 1.9 mM

    • Stress: 1.7 mM

    • Diabetic Coma: 1.7 mM

    • Prolonged Exercise: ~2 hr results in 1.8 mM.

  • Only adipocytes have the ability to release free fatty acids into the bloodstream.

TAG-rich Lipoproteins (TRLs)

  • Function: Deliver fatty acids to adipocytes and other tissues.

  • Biochemistry:

    • Triacylglycerols are delivered via Chylomicrons, VLDL.

    • Lipoprotein lipase (LPL) is involved in breaking down these lipoproteins into free fatty acids and glycerol for uptake.

Lipogenesis Details

  • Definition: Lipogenesis occurs with an energy surplus (well-fed state).

  • Two primary cytosolic processes:

    1. Fatty Acid (FA) Synthesis (De Novo Lipogenesis)

    • Primarily happens in the liver and adipose tissue.

    • Begins with Acetyl CoA; the product is Palmitate.

    1. TAG Synthesis

    • Can occur in most tissues.

      • Insulin stimulates increased lipogenesis via activation of key enzymes and transport proteins.

Pathways of Postprandial Storage of Fatty Acids

  • Re-Esterification: Involves the attachment of 3 fatty acids to glycerol to form TAG (Triglyceride).

    • Excess glucose and amino acids can synthesize fatty acids, joining with glycerol to form TAGs.

    • Insulin also stimulates adipose LPL, promoting glucose entry into cells through GLUT4.

Tissue Differences in TAG Synthesis

  • Adipose Tissue: Must use DHAP pathway (Dihydroxyacetone phosphate).

  • Liver: Utilizes Glycerol Phosphate pathway.

    • Enzyme distribution differs significantly, influencing TAG metabolism in different tissues.

Biosynthesis of Triacylglycerols

  • Activation Process: Fatty acids must be activated by forming a thioester bond with CoA (Acyl-CoA). The reaction is catalyzed by Acyl-CoA Synthetase and uses ATP as a substrate:

    • FFA+ATP+CoA<br>ightarrowAcyl−CoA+AMP+PPiFFA + ATP + CoA <br>ightarrow Acyl-CoA + AMP + PPi

  • Intermediates Involved:

    • Glycerol 3-phosphate and Dihydroxyacetone phosphate are critical intermediates connecting carbohydrate and lipid metabolism.

  • Glycerol Activation: Catalyzed by Glycerol Kinase, leading to glycerol-3-phosphate formation primarily from DHAP in tissues where glycerol kinase is absent.

Steps of TAG Biosynthesis

  1. GPAT (Glycerol Phosphate Acyltransferase):

    • Adds the first fatty acid (FA) to C1 of Glycerol.

  2. AGPAT (Acylglycerol-Phosphate Acyltransferase):

    • Adds second FA to C2, forming Phosphatidic Acid (PA).

  3. PAP (Phosphatidic Acid Phosphatase):

    • Removes phosphate from C3, forming Diacylglycerol (DAG).

  4. DGAT (Diacylglycerol Acyltransferase):

    • Adds the final FA to C3, producing TAG.

Regulation of Lipogenesis

  • Short-term Regulation:

    • Hormonal response from insulin (activates) or glucagon (inhibits).

  • Long-term Regulation:

    • Changes in gene expression influenced by nutritional states and hormonal status.

Lipolysis

  • Activation: Begins when insulin levels fall and glucagon/catecholamine levels rise.

    • Key enzymes involved: HSL (Hormone-Sensitive Lipase), ATGL (Adipose Triglyceride Lipase), MGL (Monoglyceride Lipase).

  • Process of Lipolysis:

    1. Mobilization: Fatty acids released from TAG.

    2. Circulation: Free fatty acids bound to Albumin are transported.

    3. Uptake: Fatty acids are entered into tissues for oxidation.

    4. Activation: Fatty acids transformed into Acyl-CoA, involving a cost of approximately 2 ATP.

  • Fatty Acid Transport into Mitochondria:

    1. Carnitine Acyltransferase I (CAT I): Transfers acyl from Acyl-CoA to Carnitine.

    2. Transport: Acyl-carnitine enters mitochondrial matrix.

    3. Carnitine Acyltransferase II (CAT II): Transfers fatty acyl from Carnitine back to CoA, allowing FAs to be oxidized in the TCA cycle.

Ketone Bodies and Their Regulation

  • Ketogenesis: Occurs when acetyl-CoA cannot enter the TCA cycle, leading to ketone body production from excess fatty acid oxidation.

    • Ketones spares glucose and other protein metabolism during fasting or low carbohydrate intake.

  • Metabolic Pathway: Fatty acids and ketogenic amino acids are converted to Acetyl-CoA, which can produce ketone bodies.

  • Regulation Factors Include:

    • Hepatic FFA availability, activity of CPT1, levels of malonyl CoA, and regulation by HMGCoA synthase.

Randle Cycle

  • Definition: Coined as the glucose-fatty acid cycle, it illustrates competitive inhibition where high levels of fatty acids inhibit glucose oxidation and vice versa.

  • Implications: Exercise increases the reliance on fatty acids at the expense of glucose tolerance.

Conclusion

  • Understanding lipid metabolism is crucial in nutritional biochemistry, particularly in relation to energy storage, hormonal regulation, and the body's response to fasting versus feeding states. Proper regulation of this metabolic system is essential for maintaining energy homeostasis and overall health.