Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity

Abstract

Lipids play crucial roles in signal transduction, contribute to the structural integrity of cellular membranes, and regulate energy metabolism. Questions remain as to which lipid species maintain metabolic homeostasis and which disrupt essential cellular functions, leading to metabolic disorders. Here, we discuss recent advances in understanding lipid metabolism with a focus on catabolism, synthesis, and signaling. Technical advances, including functional genomics, metabolomics, lipidomics, lipid-protein interaction maps, and advances in mass spectrometry, have uncovered new ways to prioritize molecular mechanisms mediating lipid function. By reviewing what is known about the distinct effects of specific lipid species in physiological pathways, we provide a framework for understanding newly identified targets regulating lipid homeostasis with implications for ameliorating metabolic diseases.

Keywords: cancer; cellular metabolism; free fatty acids (FFAs); lipid metabolism; lipidomics; lipids; lipotoxicity; obesity; triacylglycerol accumulation.

Figure 1. Overview of Lipid Metabolism.

(A) A systematic approach is necessary to categorize lipids as beneficial or lipotoxic. Bioactive lipid species have different roles in cellular responses, including beneficial roles in lipid homeostasis through the regulation of proliferation, storage, energy production, cell signaling, and lipid membrane composition. Lipids play a lipotoxic role by influencing cell death, ER stress, and ROS production. It is important to understand which lipid species maintain metabolic homeostasis and which disrupt essential cellular functions leading to metabolic disorders. (B) The role and structure of lipids are determined by uptake, synthesis, storage and consumption across different cellular organelles. In the anabolic pathway, lipids are taken to the ER and cytosol for lipid synthesis. For catabolism, lipids are transmitted to the mitochondria and peroxisomes. These pathways generate fatty acids, storage lipids, such as cholesterol, and triglycerides, signaling lipids containing N-acetylethanolamines (oleoylethanolamide) and cholesterol-derived bile acids. Membrane lipids include glycerophospholipids and sphingolipids. Fatty acids are building blocks of all lipids, and palmitic acid, stearic acid, oleic acid, linoleic acid, arachidonic acid, docosahexaneoic acid are illustrated as examples for saturated, monounsaturated, and polyunsaturated FAs. ABCD1, ATP Binding Cassette Subfamily D Member 1; ACAT, acyl-CoA:cholesterol acyltransferase; ATGL, adipose triglyceride lipase; CPT, carnitine palmitoyl-transferase; DGAT1, diacylglycerol O-acyltransferase 1; NPC1, Niemann Pick type-C 1; TAG, triacylglycerol.

Figure 2. Major Processes of Lipid Metabolism: uptake, synthesis, and consumption.

Lipid metabolism includes catabolic processes that generate energy, and anabolic processes that create diverse lipid species. Lipids are transmitted into cells using FA transport or translocase proteins, including FATPs and CD36. Once cells take up lipids, fatty acids are transported into the mitochondria using membrane proteins. In the mitochondria, lipids are oxidized to produce acetyl-CoA, which is further used to make ATP. Glucose uptake through glucose transporters contributes to pyruvate and acetyl-CoA to support the TCA cycle in mitochondria. Acetate uptake using MCT is another source of acetyl-CoA in the cytosol. Acetyl-CoA can affect histone and protein acetylation for epigenetic alteration in the nucleus. In addition to fatty acid oxidation in mitochondria, VLCFAs and BRCFAs are oxidized in peroxisomes contributing to TCA metabolism. Citrate is synthesized during TCA cycling and exported from the mitochondria for de novo lipogenesis (FA and cholesterol synthesis). Fatty acids can be synthesized from malonyl-CoA by fatty acid synthase. Acetyl CoA and malonylCoA are used to produce palmitate and further elongate to MUFAs and PUFAs. Long-chain fatty acids are combined into triglyceride species and stored in lipid droplets. Palmitate is converted to CDP-DAG, DAG, and triglycerides. DAG is also used in the synthesis of phospholipids for membranes, with predominant species including PC, PE, PI, and PS in ER membrane, mitochondria, and cytosol. Lipid metabolism pathways intersect to coordinate cellular metabolic state. BRCFA, branched-chain fatty acid; CDP-DAG, cytidine diphosphate diacylglycerol; DAG, diacylglycerol; ETC, electron transport chain; FA, fatty acid; FATP, fatty acid transport protein; MUFAs, monounsaturated fatty acids; PA phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; PUFA, polyunsaturated fatty acid; TCA cycle, tricarboxylic acid cycle; VLCFA, very-long-chain fatty acid.

Figure 3. Lipid homeostasis and disease.

Under conditions of excess nutrients, there is less lipolysis, conversion of triglycerides to fatty acids, in favor of increased lipogenesis or triglyceride storage in adipose tissue. In muscle cells, glucose oxidation is increased. In fasting conditions, lipolysis is increased in adipose tissue and fatty acid oxidation increases in muscle cells to provide energy. Changes in metabolism occur in the brain, heart, liver, pancreas, kidney, and adipose tissue.

Figure 4. Lipid signaling in cancer.

Lipid metabolism directly affects cancer signaling. AKT phosphorylation, the major cancer signaling pathway, activates de novo lipid biosynthesis through ACLY. This phosphorylation cascade coordinates with PA, amino acids, mTOR signaling to boost tumorigenesis, and increase SREBP transcription, resulting in fatty acid synthesis. Phospholipids and TAGs from de novo lipid biosynthesis activate proliferation and rewire membrane lipid composition by increasing saturated phospholipids. Fatty acid uptake into the nucleus directly activates cancer metastasis by nuclear receptor and the transcription factor PPAR. PUFAs induce ROS-dependent ferroptosis. Different lipid signaling employs different adaptive responses in cancer -- either survival or death. ACC2, acetyl-CoA carboxylase 2; ACLY, ATP-citrate lyase; ACSL3, acyl-CoA synthetase long-chain family member 3/4; AKT, RAC-alpha serine/threonine-protein kinase; AMPK, AMP-activated protein kinase; DAG, Diacylglycerol; DGAT1, diacylglycerol O-acyltransferase 1; FAs fatty acids; FABP5, fatty-acid binding proteins 5; FASN, fatty acid synthase; LPC, Lysophosphatidylcholine; RTK, Receptor tyrosine kinase.