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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
Lipid Enzyme Products
Triacylglycerols Lipases Monoglyceride and 2 FAs
Cholesterol esters Cholesterol ester hydrolase Cholesterol and FAs
Phospholipids Phospholipase A2 Lysolecithin and an FA

Absorption of Lipids

  • Location:
    • Majority of absorption occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine.
    • Short-chain fatty acids may be absorbed in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. 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 Cytosol A cell's cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. . The Cell: Cytosol and Cytoskeletonof 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and other tissues in the body.
  • Short-chain fatty acids (SCFAs) to medium-chain fatty acids (MCFAs):
    • In the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine, these FAs travel across the enterocyte without assistance to the hepatic portal vein, into the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, and finally into the general circulation.
    • In the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix, these FAs use the SMCT1 transporter (sodium gradient-dependent) and travel into the general circulation via the hepatic portal vein and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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
Lipoprotein Source Composition Main lipid components Apolipoproteins
Chylomicrons Intestine
  • 1%–2% protein
  • 98%–99% lipids
Triacylglycerols
  • A-I
  • A-II
  • A-IV
  • B-48
  • C-I
  • C-II
  • C-III
  • E
VLDL Liver (intestine)
  • 7%–10% protein
  • 90%–93% lipids
Triacylglycerols
  • B-100
  • C-I
  • C-II
  • C-III
LDL VLDL
  • 21% proteins
  • 79% lipids
Cholesterol B-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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the PCSK9 protease, impedes adequate clearance of LDLs and causes their accumulation in plasma. The accumulation of lipids (triacylglycerols) in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver causes nonalcoholic fatty liver disease Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease is a spectrum of liver pathology that arises due to accumulation of triglycerides in hepatocytes. Risk factors include diabetes mellitus, insulin resistance, obesity, and hypertension, among others. Nonalcoholic fatty liver disease ranges from fatty liver or hepatic steatosis but can lead to nonalcoholic steatohepatitis (NASH), which features fatty deposits and inflammation. Nonalcoholic Fatty Liver Disease. If the accumulation is chronic, causing inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, nonalcoholic steatohepatitis develops.
  • Hyperchylomicronemia: due to significantly elevated hypertriglyceridemia and chylomicrons. Presentation may be with xanthomas, hepatosplenomegaly, recurrent abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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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