Lipid Metabolism

Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component production. Lipid metabolism uses fats from dietary sources or from fat stores in the body. A complex series of processes involving digestion, absorption, and transport are required for the proper metabolism of lipids. Triacylglycerols are transported in body fluids by molecules called lipoproteins. Within the GI tract, metabolism of triacylglycerols may occur, facilitated by a group of enzymes called lipases. This process relies on preprocessing to make hydrophobic lipids soluble in order to accommodate hydrolysis and further processing.

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Overview

  • Dietary lipids: 
    • Energy-dense forms of storage
    • Provide essential fatty acids
    • Essential in absorption of fat-soluble vitamins
    • Made mostly of triacylglycerols and cholesterol
    • Can be found in 2 forms at room temperature: 
      • Fats: solid, more saturated fatty acids (FAs) 
      • Oils: liquid, more unsaturated FAs
  • Lipid sources:
    • Dietary lipids
    • Fat synthesis in liver
  • Lipid metabolism is tightly regulated:
    • Disorders in metabolism result in dyslipidemia
    • Wide-ranging health repercussions

Digestion of Lipids

  • Lipids are broken down and packaged into micelles (spherical aggregates, inside lipophilic and outside hydrophilic), which are readily absorbed by the membranes of enterocytes.
  • Lipases are key enzymes that break down triglycerides.
  • This breakdown begins in the mouth with lingual lipase, but the majority of the process occurs in the small intestine.
  • Lipases catalyze the hydrolysis of the ester bond of the triacylglycerol:
    • Intracellular: hormone-sensitive lipase in adipocytes and lysosomal lipases
    • Extracellular: pancreatic lipase, lipoprotein lipase, bile-salt–dependent lipase
  • 1 lipase for every FA in a triacylglycerol:
    • Hormone-sensitive lipase for the 1st FA
    • Diacylglycerol lipase for the 2nd FA
    • Monoacylglycerol lipase for the 3rd FA
  • Digestion occurs until these lipids are broken down into FAs, which can be absorbed by the intestine.
  • Also needed for digestion of lipids:
    • Bile salts for emulsification
    • Colipases: necessary coenzymes of lipases
Table: Lipids and their enzymes
LipidEnzymeProducts
TriacylglycerolsLipasesMonoglyceride and 2 FAs
Cholesterol estersCholesterol ester hydrolaseCholesterol and FAs
PhospholipidsPhospholipase A2Lysolecithin and an FA

Absorption of Lipids

  • Location:
    • Majority of absorption occurs in the small intestine.
    • Short-chain fatty acids may be absorbed in the stomach.
  •  Long-chain fatty acids:
    • Mixed micelles are formed and approach the brush border of the resorption cell:
      • pH change breaks these micelles down into triglycerides and cholesterol esters.
      • The micelles are now able to be absorbed.
    • FAs and monoglycerides travel across the membrane to enter the cytosol of epithelial cells.
    • Activation: takes place at the cytosolic side of the outer mitochondrial membrane
      • Acetate coenzyme A (acyl-CoA) synthetase forms activated FA.
      • Esterification: takes place in ER, where acyl-CoA bonds with monoglycerides to form triglycerides, which transport to Golgi apparatus.
    • In the Golgi apparatus, fats are repackaged as chylomicrons.
    • Chylomicrons exit the enterocyte on its basolateral side and enter the lymphatic circulation toward the liver and other tissues in the body.
  • Short-chain fatty acids (SCFAs) to medium-chain fatty acids (MCFAs):
    • In the small intestine, these FAs travel across the enterocyte without assistance to the hepatic portal vein, into the liver, and finally into the general circulation.
    • In the large intestine, these FAs use the SMCT1 transporter (sodium gradient-dependent) and travel into the general circulation via the hepatic portal vein and liver.

Transport of Lipids

Transport

  • Lipids are hydrophobic → require transport proteins (lipoproteins):
    • Lipoproteins are amphipathic, allowing these molecules to travel through the blood while carrying lipid.
    • Structure: consists of a hydrophobic core and a hydrophilic shell of varying lipids
    • Chylomicrons are an example of lipoproteins.
    • VLDLs carry triglyceride.
    • LDLs carry cholesterol.
  • Free fatty acids (FFAs) are transported by albumin:
    • Albumin has approximately 7 binding sites for FAs.
    • Albumin may facilitate uptake of FAs in organs in need of FFAs.
The lipoprotein structure facilitates transport of lipids through the blood

The lipoprotein structure facilitates transport of lipids through the blood.

Image: “Chylomicrons contain triglycerides, cholesterol molecules, and other apolipoproteins (protein molecules)” by OpenStax College. License: CC BY 4.0

Lipoproteins and their composition

Table: Lipoproteins and their composition
LipoproteinSourceCompositionMain lipid componentsApolipoproteins
ChylomicronsIntestine
  • 1%–2% protein
  • 98%–99% lipids
Triacylglycerols
  • A-I
  • A-II
  • A-IV
  • B-48
  • C-I
  • C-II
  • C-III
  • E
VLDLLiver (intestine)
  • 7%–10% protein
  • 90%–93% lipids
Triacylglycerols
  • B-100
  • C-I
  • C-II
  • C-III
LDLVLDL
  • 21% proteins
  • 79% lipids
CholesterolB-100
HDL
  • Liver
  • Intestine
  • VLDL
  • Chylomicrons
  • Phospholipids
  • Cholesterol
  • A-I
  • A-II
  • A-IV
  • C-I
  • C-II
  • C-III
  • D
  • E

Clinical Relevance

  • Lipid disorders: familial hypercholesterolemia, caused by a mutation in the PCSK9 protease, impedes adequate clearance of LDLs and causes their accumulation in plasma. The accumulation of lipids (triacylglycerols) in the liver causes nonalcoholic fatty liver disease. If the accumulation is chronic, causing inflammation, nonalcoholic steatohepatitis develops.
  • Hyperchylomicronemia: due to significantly elevated hypertriglyceridemia and chylomicrons. Presentation may be with xanthomas, hepatosplenomegaly, recurrent abdominal pain, and pancreatitis.
  • Fatty acids: molecules characterized by a carboxylic acid and an aliphatic chain. Fatty acids are either stored as fuel or are part of the cell structure. These molecules are classified according to their length, such that there are short-chain FAs, medium-chain FAs, and long-chain FAs. Fatty acids may be saturated, having no carbon double bonds, or unsaturated.

References

  1. Botham, K. M., Mayes, P. A. (2018). Lipid transport & storage. Chapter 25 of Rodwell, V.W., et al., (Eds.), Harper’s Illustrated Biochemistry, 31st ed. New York: McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?aid=1160189897
  2. Masoro, E.J. (1977). Lipids and lipid metabolism. Annu Rev Physiol 39:301–321. https://pubmed.ncbi.nlm.nih.gov/192136/
  3. Lent-Schochet, D., Jialal, I. (2021). Biochemistry, lipoprotein metabolism. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK553193/
  4. Feingold, K.R. Introduction to lipids and lipoproteins. (2000). In Feingold, K.R., et al. (Eds.), Endotext. South Dartmouth (MA): MDText.com. https://pubmed.ncbi.nlm.nih.gov/26247089/
  5. Jo, Y., Okazaki, H., Moon, Y.A., Zhao, T. (2016). Regulation of lipid metabolism and beyond. International Journal of Endocrinology 2016:5415767. https://doi.org/10.1155/2016/5415767
  6. van der Vusse, GJ. (2009). Albumin as fatty acid transporter. Drug Metab Pharmacokinet 24:300–307. https://pubmed.ncbi.nlm.nih.gov/19745557/

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