Overview of Lipid Metabolism

Overview of Lipid Metabolism

Introduction

  • Lecture 2 focuses on the overview of lipid metabolism, detailing the processes that occur during fed and fasted states, and the role of various lipoproteins.

  • Lipids are absorbed and packaged into chylomicrons that travel through the lymph and then into circulation

Fed State

Dietary Fat and Carbohydrate Digestion

  • Location: Small Intestine

  • Processes:

    • Absorbed as free fatty acids and monoglycerol

    • Reesterification of Non-Esterified Fatty Acids (NEFAs) to form Triacylglycerols (TAGs)

    • Chylomicron synthesis and secretion into the portal blood

Pathway Overview

Chylomicron Dynamics

  • Process:

    1. Chylomicron remnants and lipoproteins (Intermediate Density Lipoproteins - IDLs, and Low-Density Lipoproteins - LDLs) circulate and transport glycerol and NEFAs.

    2. De novo lipogenesis occurs particularly with high carbohydrate diets, leading to the formation of glycerol and fatty acids.

    3. Chylomicron remnants are processed in the liver.

    4. Liver also conducts VLDL synthesis

      1. VLDL triglycerides interact with lipoprotein lipase in adipose tissue

Cellular Uptake and Storage

  • Muscle Tissue:

    • Muscle Lipoprotein lipase acts on chylomicrons (TAGs) to release free fatty acids (FFAs) and glycerol.

      • Breaks ester bonds into 3 non-esterified fatty acids and a glycerol

    • Oxidation of NEFAs to carbon dioxide (CO₂) and water (H₂O).

    • Storage as Intramuscular Triglycerides (IMTG).

  • Adipose Tissue:

    • Adipose Lipoprotein Lipase (ALPL) is crucial for the hydrolysis of triglycerides into free fatty acids and glycerol, facilitating the mobilization of stored fats for energy during periods of energy demand.

    • Reesterification of NEFAs occurs, forming TAGs for storage.

  • Dietary lipids in chylomicrons, Endogenous lipids in VLDL

c Fasted State

Metabolism Changes

  • Key Components in Fasted State:

    • IDLs and LDLs circulate with associated glycerol and NEFAs.

    • Increased levels of ketone bodies, a significant source of energy during fasting.

Pathway Overview

  • Processes:

    • Esterification of NEFAs to form TAGs for VLDL synthesis and secretion.

    • Ketone body synthesis takes place in the liver, utilizing NEFAs to produce energy during fasting.

Muscle and Adipose Tissue Functions

  • Muscle Tissue:

    • Uptake of NEFAs and ketone bodies.

    • Oxidation of NEFAs and ketone bodies for energy production.

    • Lipolysis of stored IMTG to release NEFAs and glycerol.

  • Adipose Tissue:

    • Lipolysis of stored TAGs to release NEFAs and glycerol into venous blood.

    • Not much stored at all

Lipoprotein Dynamics

Formation of Triacylglycerol-Rich Lipoproteins

  • Origin: Formed in intestinal absorptive cells and liver hepatocytes.

  • Function: Secreted into circulation, interact with lipoprotein lipase (LPL) in capillaries of adipose and muscle tissue.

  • LPL Role: Hydrolyzes TAGs to release fatty acids and glycerol.

Regulation and Activity of Lipoprotein Lipase

Synthesis and Translocation of LPL

  • Synthesis Sources: Adipose tissue, heart, skeletal muscle, and lactating mammary glands.

  • Translocation: LPL is moved to the luminal side of capillary endothelial cells; requires apolipoprotein C-II as a co-factor.

  • Activation: After processing in endoplasmic reticulum (ER), it attaches to cell-surface heparan sulfate proteoglycans (HSPG).

  • Release Mechanism: Cleaved by heparanase, allowing LPL to hydrolyze TAGs in lipoproteins.

Regulation of LPL Activity

  • Tissue Specific: LPL activity is tissue-specific and varies with insulin and glucose levels.

    • Higher insulin/glucose increases LPL activity in adipose, but not muscle.

  • Angiopoietin-Related Proteins: Regulate LPL activity in response to feeding patterns, fasting, exercise, and environmental temperature.

    • Produced by liver

  • Postprandial Suppression: TAG utilization by oxidative tissues is suppressed, favoring adipose tissue TAG removal.

Fatty Acid Activation and Metabolism

Fatty Acyl-CoA Synthetase

  • Activation Process: Fatty acids from exogenous or endogenous sources must be activated to acyl-CoA for metabolism pathways.

  • Fatty-acyl CoA - is thus a critical intermediate in lipid metabolism, facilitating the conversion of fatty acids into a usable form for energy production and biosynthesis.

  • Fatty Acyl-CoA Synthetase

    • ATP + Fatty Acid + CoA → Fatty acyl-CoA + AMP + PPi

    • Energy cost is 2 ATP

  • Pyrophosphatase

    • PPi + H2O → 2 Pi

Special Types of Adipose Tissue Regulating Lipid Metabolism

Differences Between Brown and White Adipose Tissues

  • Brown Adipose Tissue: Specialized in energy expenditure and thermogenesis.

  • White Adipose Tissue: Primarily stores energy in the form of fat.

Hepatic Triacylglycerol Lipase (HTGL)

Functionality

  • Hydrolyzes remaining TAGs in chylomicron (CM) and VLDL remnants.

  • Similar structure and function to LPL.

  • {FFA} and glycerol produced in the liver can be re-esterified and repackaged into VLDLs.