Meta-Biol

• Pathways

Triacylglycerol is a major energy store in the body and its hydrolysis to yield fatty acids and glycerol is a tightly regulated part of energy metabolism. A central part in this regulation is played by hormone-sensitive lipase (HSL), a neutral lipase abundant in adipocytes and skeletal and cardiac muscle, but also abundant in ovarian and adrenal tissue, where it mediates cholesterol ester hydrolysis, yielding cholesterol for steroid biosynthesis. The hormones to which it is sensitive include catecholamines (e.g., epinephrine), ACTH, and glucagon, all of which trigger signaling cascades that lead to its phosphorylation and activation, and insulin, which sets off events leading to its dephosphorylation and inactivation (Holm et al. 2000; Kraemer and Shen 2002).

The processes of triacylglycerol and cholesterol ester hydrolysis are also regulated by subcellular compartmentalization: these lipids are packaged in cytosolic particles and the enzymes responsible for their hydrolysis, and perhaps for additional steps in their metabolism, are organized at the surfaces of these particles (e.g., Brasaemle et al. 2004). This organization is dynamic: the inactive form of HSL is not associated with the particles, but is translocated there after being phosphorylated. Conversely, perilipin, a major constituent of the particle surface, appears to block access of enzymes to the lipids within the particle; its phosphorylation allows greater access.

Here, HSL-mediated triacylglycerol hydrolysis is described as a pathway containing twelve reactions. The first six of these involve activation: phosphorylation of HSL, dimerization of HSL, disruption of CGI-58:perilipin complexes at the surfaces of cytosolic lipid particles, phosphorylation of perilipin, association of phosphorylated HSL with FABP, and translocation of HSL from the cytosol to the surfaces of lipid particles. The next four reactions are the hydrolysis reactions themselves: the hydrolysis of cholesterol esters, and the successive removal of three fatty acids from triacylglycerol. The last two reactions, dephosphorylation of perilipin and HSL, negatively regulate the pathway. These events are outlined in the figure below. Inputs (substrates) and outputs (products) of individual reactions are connected by black arrows; blue lines connect output activated enzymes to the other reactions that they catalyze.

Despite the undoubted importance of these reactions in normal human energy metabolism and in the pathology of diseases such as type II diabetes, they have been studied only to a limited extent in human cells and tissues. Most experimental data are derived instead from two rodent model systems: primary adipocytes from rats, and mouse 3T3-L1 cells induced to differentiate into adipocytes.

Lipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphingolipids, eicosanoids, cholesterol, bile salts, steroid hormones, and fat-soluble vitamins. They function as a major source of energy (fatty acids, triacylglycerols, and ketone bodies), are major constituents of cell membranes (cholesterol and phospholipids), play a major role in their own digestion and uptake (bile salts), and participate in numerous signaling and regulatory processes (steroid hormones, eicosanoids, phosphatidylinositols, and sphingolipids) (Vance & Vance 2008 - URL).

The central steroid in human biology is cholesterol, obtained from animal fats consumed in the diet or synthesized de novo from acetyl-coenzyme A. (Vegetable fats contain various sterols but no cholesterol.) Cholesterol is an essential constituent of lipid bilayer membranes and is the starting point for the biosyntheses of bile acids and salts, steroid hormones, and vitamin D. Bile acids and salts are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual development and function (androgens and estrogens). At the same time, chronically elevated cholesterol levels in the body are associated with the formation of atherosclerotic lesions and hence increased risk of heart attacks and strokes. The human body lacks a mechanism for degrading excess cholesterol, although an appreciable amount is lost daily in the form of bile salts and acids that escape recycling.

Aspects of lipid metabolism currently annotated in Reactome include lipid digestion, mobilization, and transport; fatty acid, triacylglycerol, and ketone body metabolism; peroxisomal lipid metabolism; phospholipid and sphingolipid metabolism; cholesterol biosynthesis; bile acid and bile salt metabolism; and steroid hormone biosynthesis.

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.

At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.