Lipogenesis

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In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. [1] Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. [2] [3] A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. [4] After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

Contents

Fatty acid synthesis

Fatty acid synthesis starts with acetyl-CoA and builds up by the addition of two-carbon units. Fatty acid synthesis occurs in the cytoplasm of cells while oxidative degradation occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthase. [5] The major sites of fatty acid synthesis are adipose tissue and the liver. [6]

Triglyceride synthesis

Triglycerides are synthesized by esterification of fatty acids to glycerol. [1] Fatty acid esterification takes place in the endoplasmic reticulum of cells by metabolic pathways in which acyl groups in fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol. [7] Three fatty acid chains are bonded to each glycerol molecule. Each of the three -OH groups of the glycerol reacts with the carboxyl end of a fatty acid chain (-COOH). Water is eliminated and the remaining carbon atoms are linked by an -O- bond through dehydration synthesis.

Both the adipose tissue and the liver can synthesize triglycerides. Those produced by the liver are secreted from it in the form of very-low-density lipoproteins (VLDL). VLDL particles are secreted directly into blood, where they function to deliver the endogenously derived lipids to peripheral tissues.

Hormonal regulation

Insulin is a peptide hormone that is critical for managing the body's metabolism. Insulin is released by the pancreas when blood sugar levels rise, and it has many effects that broadly promote the absorption and storage of sugars, including lipogenesis.

Insulin stimulates lipogenesis primarily by activating two enzymatic pathways. Pyruvate dehydrogenase (PDH), converts pyruvate into acetyl-CoA. Acetyl-CoA carboxylase (ACC), converts acetyl-CoA produced by PDH into malonyl-CoA. Malonyl-CoA provides the two-carbon building blocks that are used to create larger fatty acids.

Insulin stimulation of lipogenesis also occurs through the promotion of glucose uptake by adipose tissue. [1] The increase in the uptake of glucose can occur through the use of glucose transporters directed to the plasma membrane or through the activation of lipogenic and glycolytic enzymes via covalent modification. [8] The hormone has also been found to have long term effects on lipogenic gene expression. It is hypothesized that this effect occurs through the transcription factor SREBP-1, where the association of insulin and SREBP-1 lead to the gene expression of glucokinase. [9] The interaction of glucose and lipogenic gene expression is assumed to be managed by the increasing concentration of an unknown glucose metabolite through the activity of glucokinase.

Another hormone that may affect lipogenesis through the SREBP-1 pathway is leptin. It is involved in the process by limiting fat storage through inhibition of glucose intake and interfering with other adipose metabolic pathways. [1] The inhibition of lipogenesis occurs through the down regulation of fatty acid and triglyceride gene expression. [10] Through the promotion of fatty acid oxidation and lipogenesis inhibition, leptin was found to control the release of stored glucose from adipose tissues. [1]

Other hormones that prevent the stimulation of lipogenesis in adipose cells are growth hormones (GH). Growth hormones result in loss of fat but stimulates muscle gain. [11] One proposed mechanism for how the hormone works is that growth hormones affects insulin signaling thereby decreasing insulin sensitivity and in turn down regulating fatty acid synthase expression. [12] Another proposed mechanism suggests that growth hormones may phosphorylate with STAT5A and STAT5B, transcription factors that are a part of the Signal Transducer And Activator Of Transcription (STAT) family. [13]

There is also evidence suggesting that acylation stimulating protein (ASP) promotes the aggregation of triglycerides in adipose cells. [14] This aggregation of triglycerides occurs through the increase in the synthesis of triglyceride production. [15]

PDH dephosphorylation

Insulin stimulates the activity of pyruvate dehydrogenase phosphatase. The phosphatase removes the phosphate from pyruvate dehydrogenase activating it and allowing for conversion of pyruvate to acetyl-CoA. This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-CoA. Increased levels of acetyl-CoA will increase the flux through not only the fat synthesis pathway but also the citric acid cycle.

Acetyl-CoA carboxylase

Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation via activation of PP2A phosphatase whose activity results in the activation of the enzyme. Glucagon has an antagonistic effect and increases phosphorylation, deactivation, thereby inhibiting ACC and slowing fat synthesis.

Affecting ACC affects the rate of acetyl-CoA conversion to malonyl-CoA. Increased malonyl-CoA level pushes the equilibrium over to increase production of fatty acids through biosynthesis. Long chain fatty acids are negative allosteric regulators of ACC and so when the cell has sufficient long chain fatty acids, they will eventually inhibit ACC activity and stop fatty acid synthesis.

AMP and ATP concentrations of the cell act as a measure of the ATP needs of a cell. When ATP is depleted, there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC and thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low.

ACC is also activated by citrate. When there is abundant acetyl-CoA in the cell cytoplasm for fat synthesis, it proceeds at an appropriate rate.

Transcriptional regulation

SREBPs have been found to play a role with the nutritional or hormonal effects on the lipogenic gene expression. [16]

Overexpression of SREBP-1a or SREBP-1c in mouse liver cells results in the build-up of hepatic triglycerides and higher expression levels of lipogenic genes. [17]

Lipogenic gene expression in the liver via glucose and insulin is moderated by SREBP-1. [18] The effect of glucose and insulin on the transcriptional factor can occur through various pathways; there is evidence suggesting that insulin promotes SREBP-1 mRNA expression in adipocytes [19] and hepatocytes. [20] It has also been suggested that the hormone increases transcriptional activation by SREBP-1 through MAP-kinase-dependent phosphorylation regardless of changes in the mRNA levels. [21] Along with insulin glucose also have been shown to promote SREBP-1 activity and mRNA expression. [22]

Related Research Articles

<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production. Coenzyme A consists of a β-mercaptoethylamine group linked to the vitamin pantothenic acid (B5) through an amide linkage and 3'-phosphorylated ADP. The acetyl group of acetyl-CoA is linked to the sulfhydryl substituent of the β-mercaptoethylamine group. This thioester linkage is a "high energy" bond, which is particularly reactive. Hydrolysis of the thioester bond is exergonic (−31.5 kJ/mol).

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Ketogenesis</span> Chemical breakdown of ketone bodies

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Pyruvate carboxylase</span>

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Acetyl-CoA carboxylase</span> Enzyme that regulates the metabolism of fatty acids

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the cytoplasm of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids. The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs—ACACA and ACACB.

<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

In chemistry, de novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to recycling after partial degradation. For example, nucleotides are not needed in the diet as they can be constructed from small precursor molecules such as formate and aspartate. Methionine, on the other hand, is needed in the diet because while it can be degraded to and then regenerated from homocysteine, it cannot be synthesized de novo.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

<span class="mw-page-title-main">White adipose tissue</span> Fatty tissue composed of white adipocytes

White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.

<span class="mw-page-title-main">Stearoyl-CoA 9-desaturase</span> Class of enzymes

Stearoyl-CoA desaturase (Δ-9-desaturase) is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs), specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA. Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and alkyl-diacylglycerol. In humans, the enzyme is encoded by the SCD gene.

<span class="mw-page-title-main">Sterol regulatory element-binding protein 1</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the SREBF1 gene.

<span class="mw-page-title-main">Carbohydrate-responsive element-binding protein</span> Protein-coding gene in the species Homo sapiens

Carbohydrate-responsive element-binding protein (ChREBP) also known as MLX-interacting protein-like (MLXIPL) is a protein that in humans is encoded by the MLXIPL gene. The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.

<span class="mw-page-title-main">INSIG2</span>

Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.

Fructolysis refers to the metabolism of fructose from dietary sources. Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is directly metabolized widely in the body, fructose is almost entirely metabolized in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body.

Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate or triglyceride from precursors other than glucose. Usually glycerol 3-phosphate is generated from glucose by glycolysis, but when glucose concentration drops in the cytosol, it is generated by another pathway called glyceroneogenesis. Glyceroneogenesis uses pyruvate, alanine, glutamine or any substances from the TCA cycle as precursors for glycerol 3-phosphate. Phosphoenolpyruvate carboxykinase (PEPC-K), which is an enzyme that catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate is the main regulator for this pathway. Glyceroneogenesis can be observed in adipose tissue and also in the liver. It is a significant biochemical pathway that regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorders such as type 2 diabetes.

References

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  2. ↑ Hoffman, Simon; Alvares, Danielle; Adeli, Khosrow (2019). "Intestinal lipogenesis: how carbs turn on triglyceride production in the gut". Current Opinion in Clinical Nutrition and Metabolic Care. 22 (4): 284–288. doi:10.1097/MCO.0000000000000569. ISSN   1473-6519. PMID   31107259. S2CID   159039179.
  3. ↑ Figueroa-Juárez, Elizabeth; Noriega, Lilia G.; Pérez-Monter, Carlos; Alemán, Gabriela; Hernández-Pando, Rogelio; Correa-Rotter, Ricardo; Ramírez, Victoria; Tovar, Armando R.; Torre-Villalvazo, Iván; Tovar-Palacio, Claudia (2021-01-07). "The Role of the Unfolded Protein Response on Renal Lipogenesis in C57BL/6 Mice". Biomolecules. 11 (1): 73. doi: 10.3390/biom11010073 . ISSN   2218-273X. PMC   7825661 . PMID   33430288.
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  16. ↑ Hua, X; Yokoyama, C; Wu, J; Briggs, M R; Brown, M S; Goldstein, J L; Wang, X (1993-12-15). "SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element". Proceedings of the National Academy of Sciences of the United States of America. 90 (24): 11603–11607. Bibcode:1993PNAS...9011603H. doi: 10.1073/pnas.90.24.11603 . ISSN   0027-8424. PMC   48032 . PMID   7903453.
  17. ↑ Horton, J. D.; Shimomura, I. (1999-04-01). "Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis". Current Opinion in Lipidology. 10 (2): 143–150. doi:10.1097/00041433-199904000-00008. ISSN   0957-9672. PMID   10327282.
  18. ↑ Shimano, H.; Yahagi, N.; Amemiya-Kudo, M.; Hasty, A. H.; Osuga, J.; Tamura, Y.; Shionoiri, F.; Iizuka, Y.; Ohashi, K. (1999-12-10). "Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes". The Journal of Biological Chemistry. 274 (50): 35832–35839. doi: 10.1074/jbc.274.50.35832 . ISSN   0021-9258. PMID   10585467.
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  20. ↑ Foretz, Marc; Pacot, Corinne; Dugail, Isabelle; Lemarchand, Patricia; Guichard, Colette; le Lièpvre, Xavier; Berthelier-Lubrano, Cécile; Spiegelman, Bruce; Kim, Jae Bum (1999-05-01). "ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose". Molecular and Cellular Biology. 19 (5): 3760–3768. doi:10.1128/mcb.19.5.3760. ISSN   0270-7306. PMC   84202 . PMID   10207099.
  21. ↑ Roth, G.; Kotzka, J.; Kremer, L.; Lehr, S.; Lohaus, C.; Meyer, H. E.; Krone, W.; Müller-Wieland, D. (2000-10-27). "MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro". The Journal of Biological Chemistry. 275 (43): 33302–33307. doi: 10.1074/jbc.M005425200 . ISSN   0021-9258. PMID   10915800.
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