Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Liver
The Role of the Liver in Lipid Metabolism

The hepatic enzyme systems are capable of catalyzing all or a significant majority of Lipid METABOLISM reactions. The aggregate of these reactions underlies such key processes as the synthesis of Higher Fatty acids, triglycerides, Phospholipids, Cholesterol and its esters, as well as the lipolysis of triglycerides, the Oxidation of Fatty acids, The formation of acetone (ketone) bodies, and more.

Recall that the enzymatic pathways for triglyceride synthesis in The Liver and adipose tissue are similar. Specifically, long-chain fatty acyl-CoA derivatives react with glycerol-3-phosphate to yield phosphatidic acid, which is subsequently hydrolyzed to a diglyceride. The addition of another fatty acyl-CoA molecule to the latter produces a triglyceride. Triglycerides synthesized in the liver either remain hepatic stores or are secreted into the bloodstream as Lipoproteins. This secretion occurs with a noticeable delay (1–3 hours in humans), which presumably corresponds to the time required for lipoprotein assembly.

As noted, the liver is the primary site for the formation of plasma pre-ß-lipoproteins (very low-density lipoproteins, or VLDL) and α-lipoproteins (high-density lipoproteins, or HDL).

Let us examine VLDL formation. According to literature, apolipoprotein B-100 (apo B-100), the main protein component of these lipoproteins, is synthesized in the Ribosomes of the rough Endoplasmic reticulum within hepatocytes. VLDL assembly takes place in the smooth endoplasmic reticulum, where lipid components are also synthesized. One of the primary triggers for VLDL formation is an elevated concentration of non-esterified fatty acids (NEFAs). These acids either reach the liver via the bloodstream bound to albumin or are synthesized de novo in the liver. NEFAs serve as the principal source for triglyceride (TG) production. Information regarding NEFA and TG levels is transmitted to the membrane-bound ribosomes of the rough endoplasmic reticulum, which in turn signals the Synthesis of the protein apo B-100. The newly synthesized protein is embedded into the membrane of the rough reticulum; following interaction with the phospholipid bilayer, a region consisting of phospholipids (PL) and protein buds off from the membrane, serving as a precursor to the lipoprotein particle. Next, this protein-phospholipid complex moves to the smooth endoplasmic reticulum, where it interacts with TGs and esterified cholesterol (EC). Subsequent structural reorganizations yield nascent, or immature, particles (n-VLDL). These particles travel through the tubular network of the Golgi apparatus into secretory vesicles, which transport them to The Cell surface, where they are released into the perisinusoidal spaces (Disse spaces) via exocytosis. From the Disse spaces, n-VLDL particles enter the lumen of the Blood sinusoid; here, apolipoproteins C are transferred from HDL to n-VLDL, completing the maturation of the latter particles (Fig. 16.3). The total time required for apo B-100 synthesis, lipid-protein complex formation, and the secretion of mature VLDL particles has been established to be approximately 40 minutes.

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Fig. 16.3. Formation of very low-density lipoproteins (VLDL) in a hepatic cell (based on A.N. Klimov and N.G. Nikulcheva).

1 - Nucleus; 2 - rough endoplasmic reticulum; 3 - smooth endoplasmic reticulum, along with its synthesized Lipids and nascent VLDL (n-VLDL) particles; 4 - Golgi apparatus; 5 - secretory vesicle containing an n-VLDL particle; 6 - n-VLDL particle in the Disse space; 7 - transfer of apolipoproteins C from HDL to n-VLDL; 8 - mature VLDL particle.

In humans, the bulk of ß-lipoproteins (low-density lipoproteins, or LDL) is generated in Blood Plasma from VLDL through the action of lipoprotein lipase. This process first produces short-lived intermediate-density lipoproteins (IDLs), which subsequently mature into particles depleted of triglycerides and enriched in cholesterol—namely, LDLs.

When plasma fatty acid levels are high, their hepatic uptake increases, thereby accelerating both triglyceride synthesis and Fatty acid oxidation, which can lead to elevated ketone body production.

It should be emphasized that Ketone Bodies are produced in the liver via the so-called ß-hydroxy-ß-methylglutaryl-CoA pathway. However, it is also believed that acetoacetyl-CoA, the starting compound for ketogenesis, can originate either directly from the ß-Oxidation of fatty acids or through the Condensation of acetyl-CoA [Murray et al., 1993]. From the liver, ketone bodies are transported via the bloodstream to various Tissues and Organs (such as skeletal Muscles, Kidneys, and the Brain), where they are rapidly oxidized through the action of specific Enzymes; thus, the liver acts as an exception compared to other tissues.

The liver exhibits high rates of both phospholipid degradation and synthesis. In addition to glycerol and fatty acids, which make up neutral fats, phospholipid synthesis requires inorganic phosphates and nitrogenous compounds—specifically Choline, for the synthesis of phosphatidylcholine. Inorganic phosphates are present in the liver in adequate amounts. However, if choline is deficient or insufficiently supplied to the liver, phospholipid synthesis from neutral fat components either halts or drops sharply, causing neutral fat to accumulate in the liver. This condition is referred to as fatty infiltration of the liver, which may subsequently progress to fatty degeneration (steatosis). In other words, phospholipid synthesis is limited by the availability of nitrogenous bases; thus, the synthesis of phosphoglycerides requires either choline or compounds capable of acting as methyl Donors to participate in choline formation (e.g., Methionine). Such compounds are known as lipotropic agents. This explains why cottage cheese, which contains the milk protein casein rich in methionine amino acid residues, is highly beneficial in cases of hepatic fatty infiltration.

Let us now consider The Role of liver in steroid metabolism, specifically Cholesterol Metabolism. While a portion of cholesterol is obtained from the diet, a significantly larger amount is synthesized within the liver from acetyl-CoA. Hepatic Cholesterol Biosynthesis is inhibited by exogenous cholesterol, meaning cholesterol derived from dietary sources.

Thus, hepatic cholesterol biosynthesis is regulated via negative feedback. The greater the Dietary intake of cholesterol, the less is synthesized in the liver, and vice versa. It is generally accepted that the inhibitory effect of exogenous cholesterol on its hepatic biosynthesis is mediated by the suppression of the ß-hydroxy-ß-methylglutaryl-CoA reductase reaction:

A portion of the cholesterol synthesized in the liver is excreted from the body via Bile, while another portion is converted into bile acids and utilized in other organs for the synthesis of Steroid Hormones and various Other Compounds.

In the liver, cholesterol can react with fatty acids (in the form of acyl-CoA) to yield cholesterol esters. These hepatic cholesterol esters are then released into the blood, which also carries a certain amount of unesterified (free) cholesterol.