BIOCHEMISTRY - Textbook - L. I. Ostapchenko - 2012

Chapter 14. LIPID METABOLISM

14.5. Synthesis and Breakdown of Fats in Tissues

Fatty acids synthesized de novo or delivered to animal Tissues via the Hydrolysis of Blood lipoprotein triacylglycerols (chylomicrons and very-low-density Lipoproteins) do not accumulate in tissues in a free state because they are rapidly converted into a compact and convenient storage form: fats.

The most active fat synthesis occurs during the absorptive period, driven by high blood glucose concentrations in the Liver, adipose tissue, and other Organs.

The precursors of triacylglycerols are activated forms of glycerol and Higher Fatty Acids. The active form of glycerol, glycerol-3-phosphate, can be formed via two pathways: the phosphorylation of free glycerol or the reduction of dihydroxyacetone phosphate. In the Cells of the liver, Kidneys, and intestinal mucosa, where active glycerol kinase is present, glycerol is phosphorylated by the γ-phosphate group of ATP:

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In adipose tissue cells, Muscles, and the liver, glycerol-3-phosphate is produced through the reduction of dihydroxyacetone phosphate, a reaction catalyzed by glycerol-3-phosphate dehydrogenase:

The Enzymes responsible for triacylglycerol Biosynthesis are associated into the triacylglycerol synthase complex, which is localized on the membranes of The Endoplasmic reticulum.

The activation of fatty acids destined for lipid synthesis is catalyzed by acyl-CoA synthases:

In subsequent reactions, these activated fatty acids, in the form of CoA esters, are transferred to glycerol-3-phosphate by glycerolphosphate acyltransferase:

The reaction product, diacylglycerol-3-phosphate (or phosphatidic acid), is formed via an intermediate metabolite, lysophosphatidate.

During triacylglycerol synthesis, phosphatidate is dephosphorylated by phosphatidate phosphatase to yield 1,2-diacylglycerol, which is then converted into triacylglycerol via an acylation reaction catalyzed by diacylglycerol acyltransferase:

Fat synthesis is most intensive in The Liver and adipose tissue. Triacylglycerols synthesized in the liver are primarily utilized in other tissues, to which they are transported as components of Blood Plasma lipoproteins. Triacylglycerols produced in adipose tissue accumulate within adipocyte Cytoplasm as lipid droplets. Stored triacylglycerols account for approximately 65% of the total tissue mass. Under normal physiological conditions and with adequate caloric intake, these deposited fats serve as a long-term metabolic energy reserve, while blood lipoproteins continuously supply immediate fatty acid needs to peripheral tissues. Consequently, a dynamic equilibrium is established in adult humans and animals between the rates of fat biosynthesis and breakdown within fat depots. Adipose tissue is characterized by high metabolic activity; thus, despite a relatively constant total fat content, triacylglycerol reserves undergo a continuous turnover, with complete renewal taking place over the course of several days.

When caloric intake increases, during overeating, or when Energy Expenditure drops (hypodynamia), excess calories are channeled into fat synthesis regardless of the diet's composition (whether rich in CARBOHYDRATES, Proteins, or mixed). Conversely, under conditions of heightened energy demands, prolonged fasting, or severe stress, the reserves of triacylglycerol in adipose tissue decline due to mobilization that outpaces biosynthesis.

Fat mobilization refers to The process of triacylglycerol hydrolysis (lipolysis) catalyzed by intracellular lipase. The activity of adipose tissue lipase is hormonally regulated (Fig. 14.8). Hormones such as ACTH, adrenaline, noradrenaline, and Glucagon stimulate lipase activity via the adenylate cyclase system by elevating cAMP levels. Lipolysis is also activated by THYROID HORMONES, which inhibit cyclic nucleotide phosphodiesterase activity, thereby maintaining high intracellular cAMP concentrations. cAMP activates cAMP-dependent protein kinase, which phosphorylates inactive lipase, converting it into active lipase a. As a result of lipolysis driven by this hormone-sensitive lipase, glycerol and free Fatty acids are released from adipocytes into the bloodstream:

Glycerol is utilized by the liver as a substrate for Gluconeogenesis, whereas fatty acids are transported by blood albumins, which act as carriers delivering fatty acids from adipose tissue to peripheral tissues where they serve as an energy substrate. Insulin and prostaglandin E block the hormonal stimulation of adenylate cyclase, thereby inhibiting lipolysis.

Fig. 14.8. Hormonal Regulation of fat mobilization from adipose tissue:

AC - adenylate cyclase; PDE - cyclic nucleotide phosphodiesterase;

PPK — phosphoprotein kinase; TAG — triacylglycerols

Hormone-sensitive cAMP-dependent triacylglycerol lipase is a lipoprotein composed of protein (48%), Phospholipids (45%), and Cholesterol (6%). The Active Site of the enzyme contains a Serine residue, which is why the lipase, like other "serine" enzymes, is inhibited by sodium fluoride and organophosphorus compounds.