Research Area

Lipid Metabolism and Enzymes


Lipid Metabolism and Enzymes Overview

Lipid metabolism is the process that most of the fat ingested by the body is emulsified into small particles by bile and then the lipase secreted by the pancreas and small intestine hydrolyzes the fatty acids in the fat into free fatty acids and monoglycerides. A small amount of fatty acids is completely hydrolyzed into glycerol and fatty acids. After hydrolysis these small molecules, such as glycerol, short-chain and medium-chain fatty acids, are absorbed into the blood by the small intestine. After the absorption of monoglycerides and long-chain fatty acids, triglycerides will be re-synthesized in small intestinal cells and along with phospholipids, cholesterol and proteins to form chylomicron which will enter the blood circulation from the lymphatic system. The liver and pancreas are important sites for lipid metabolism and play an important role in the process of lipid digestion, absorption, synthesis, decomposition and transport.

Lipids are a general term for fats and lipoids and their derivatives (Figure 1). Fat is triglyceride, also known as triacylglycerol (TG); lipoids include phospholipids (PL), glycolipids; cholesterol (Ch) includes free cholesterol (FC) and cholesterol ester (CE). In normal people, the amount of lipids accounts for 25% of body weight, and most of them are stored in adipose tissue in the form of triglycerides, which are variable lipids. Lipoid is the basic structure of the tissue, called basic or fixed fat, accounting for 5% of the total lipid content. The lipids present in various tissues are body fats, and the body fat stores huge energy. When the body heat is insufficient, body fat can be used for energy consumption. A small number of lipids present in the blood circulation are blood lipids which are mainly phospholipids, triglycerides, cholesterol, free fatty acids, and trace amounts of fat-soluble vitamins and steroid hormones. Free fatty acids are mainly decomposed by TG in body fat and then enter the blood circulation.

Lipids are commonly subdivided into four main groups.

Figure 1. Lipids are commonly subdivided into four main groups.

Lipids are insoluble in water, and lipids in plasma can only be transported to the body throughout the blood cycle by binding to proteins and becoming hydrophilic. Free fatty acids bind to albumin while the remaining lipids combine with globulin to form lipoproteins. Lipoproteins containing more TG are with low density, and those containing less TG have higher density. According to the density of lipoproteins, plasma lipoproteins can be divided into four categories: (1) chylomicrons (CM); (2) very low density lipoprotein (VLDL); (3) low density lipoprotein (LDL); 4) high density lipoprotein (HDL). After binding to lipids, proteins take part in transporting lipids in plasma, so they are called apolipoproteins.

Lipid Metabolism and Enzymes in Liver

Lipid metabolism in liver.

Figure 2. Lipid metabolism in liver.

The mainly lipid source of the liver is food. The lipids in food are mainly TG, and there are a small amount of PL and Ch. In the small intestine, bile acids and pancreatic enzymes (including pancreatic lipase, phospholipase A2, cholesterol esterase, etc.) in bile hydrolyze lipids into free fatty acids (FFA), glycerol and Fc. Then these molecules are absorbed by mucosal epithelial cells of the small intestine (mainly jejunum), and are further esterified into TG, CE, etc. in intestinal epithelial cells. Finally, TG, Ch and PL with apolipoprotein compose of lipoprotein chylomicron (CM) which will be absorbed by the lymphatic system and hydrolyzed by lipoproteinase of vascular endothelial cells to enter the liver. FFA can be converted into energy by oxidation in hepatocytes for the consumption, or re-synthesize TG, PL and CE with 3-phosphoglycerate.

The mainly source of endogenous fatty acids is the fat stored in the body's adipose tissue. The fat in the fat cells is hydrolyzed into glycerol and fatty acids by the action of lipase. After being released into the blood, glycerol is dissolved in plasma while fatty acids are combined with plasma albumin for transport. It can be used as a source of energy or ingested by liver cells again. In addition, hepatocytes also can produce fatty acids from the oxidation process of glucose and amino acids and synthesize TG by acetyl-CoA in hepatocytes.

In addition to ingesting the exogenous cholesterol from food, liver cells also synthesize endogenous cholesterol. Hepatocyte endoplasmic reticulum cholesterol biosynthesis involves more than 30 enzymes, such as acetoacetyl CoA. Endogenously synthesized cholesterol and exogenous free cholesterol taken up by lipoprotein receptors must be transported through the liver. The transport destinations are: (1) decomposition into primary bile acid and bile salts in the liver, then discharging into the capillary bile duct and bile through the transport pump on the capillary bile duct; (2) free cholesterol and phospholipids are directly excreted to the bile by multi-drug resistance transporter (MDR); (3) cholesterol ester and free cholesterol are converted to each other to form dynamic equilibrium. Free cholesterol can be esterified into cholesterol ester by cholesterol acyltransferase (ACAT) and transported to the peripheral circulation in the form of VLDL. Cholesterol esters can be rapidly hydrolyzed to free cholesterol by cholesteryl ester hydrolase (CEH) as a precursor for the synthesis of bile acids; (4) VLDL consisting of apolipoproteins, phospholipids, etc. reverses into human blood circulation, reaching hepatic stellate cells and steroid hormone secreting cells.

Lipid Metabolism and Enzymes in Pancreas

Lipid metabolism in pancreas.

Figure 3. Lipid metabolism in pancreas.

Pancreatic lipase is mainly secreted by pancreatic acinar cells and functions to digest the fat in the duodenum, including the classic pancreatic triglyceride lipase (PTL), pancreatic lipase-related protein 1 (PLRP1) and 2 (PLRP2), bile salt-stimulated lipase (BSSL) and pancreatic phospholipase A2 (PLA2), etc. There are 68% and 65% amino acid sequence homology between PLRP1 and PLRP2 to PTL, respectively. The source of pancreatic lipase is quite extensive. As the research progresses, it has been reported that PLRP2 is also expressed in lymphocytes and colonic epithelial cells, which are involved in the inflammatory response and regulating the intestinal flora, respectively. The mammary gland of some mammals including humans, can secrete BSSL during lactation, which can be supplied to infants through milk to participate in their early fat digestion and absorption. It has also been found that BSSL is expressed in other tissues including liver, inflammatory cells, endothelial cells and platelets, suggesting that BSSL may be involved in the process of inflammation, arteriosclerosis, etc. These important pancreatic lipases participant in the digestion of lipids (such as triglycerides, cholesterol, and phospholipids), so that dietary fat can be fully utilized.

References:

  1. Han Y, Willis M S. The Role of PCSK9 in Lipid Metabolism and its Relationship to New Therapies for Lowering Cholesterol and Reducing Cardiac Disease. Journal of Cardiology and Therapy. 2015, 2(5):393-399.
  2. Huang C, Freter C. Lipid Metabolism, Apoptosis and Cancer Therapy. International Journal of Molecular Sciences. 2015, 16(1):924-949.
  3. Nguyen P, et al. Liver lipid metabolism. Journal of Animal Physiology & Animal Nutrition. 2010, 92(3):272-283.
  4. Sunami Y, et al. Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells. Cancers. 2018, 10(1):3.

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