Lipid Metabolism–Signaling Crosstalk in Metabolic Disease and Aging: Mechanisms and Therapeutic Targets
1GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, India
2Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea; awdhesh@ynu.ac.kr
3Symbiosis Centre for Information Technology (SCIT), Symbiosis International (Deemed University), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune 411057, India; krishnakumar@scit.edu
4GL Bajaj Institute of Technology and Management, Greater Noida 201308, India
5Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA; rstojchevski@northwell.edu
6Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
7Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
*Correspondence: davtanski@northwell.edu (D.A.); jksinha@gloneuro.org (J.K.S.); Tel.: +1-(212)-434-3552 (D.A.); +91-8919679822 (J.K.S.)Abstract
Lipid metabolism and lipid-derived signaling together ensure cellular and systemic homeostasis. Their dysregulation causes obesity, type 2 diabetes, cardiovascular disease, NAFLD/MASH, and neurodegeneration throughout life. This review integrates central pathways, such as ACC–FASN-mediated de novo lipogenesis, lipid-droplet lipolysis, and mitochondrial and peroxisomal β-oxidation, and their regulation by insulin–PI3K–Akt, glucagon–cAMP–PKA, SREBPs, PPARs, and AMPK. We emphasize the mechanisms by which bioactive lipids like diacylglycerols, ceramides, eicosanoids, and endocannabinoids serve as second messengers linking nutrient state to insulin signaling, inflammation, and stress response; pathologic accumulation of these species enhances insulin resistance and lipotoxicity. Aging disrupts these axes via diminished catecholamine-stimulated lipolysis, defective fatty-acid oxidation, mitochondrial failure, and adipose depot redistribution, facilitating ectopic fat and postprandial dyslipidemia. We suggest a pathway-to-phenotype paradigm that connects lipid species and tissue environment to clinical phenotypes, allowing for mechanism-to-intervention alignment. Therapeutic avenues range from lipid lowering for atherogenic risk to novel agents targeting ACLY, ACC, FASN, CPT1, and nuclear receptors, with precision lifestyle intervention in diet and exercise. Translation is still heterogeneous because of isoform-dependent effects, safety trade-offs, and inconsistent adherence. We prioritize harmonization of lipidomics with multi-omics for stratifying patients, enriching responders, and bridging gaps between mechanistic understanding and clinical outcome, with focus on age-sensitive prevention and treatment for lipid-mediated metabolic disease.
1. Introduction
Our lifestyle choices considerably impact our metabolic health, which can consequently result in a range of disorders [1]. Lipids, vital to metabolic processes, fulfil numerous essential functions within the human body. They act as structural components of cells, serve as energy reserves, participate in signaling pathways, function as biomarkers, contribute to energy metabolism, and serve as hormones. Disruption of these lipid-related processes may initiate a cascade of interconnected health issues, including diabetes, infections, as well as inflammatory and neurodegenerative diseases [2]. Lipids are organic compounds that don’t dissolve in water but do dissolve in organic solvents. These compounds are classic esters of fatty acids and sometimes include alcohol or phosphate functional groups. Lipids cover a range of molecules, such as triglycerides, phospholipids, and steroids. They serve as the primary energy reserves in animals, help regulate body temperature, form the essential components of cell membranes, and act as chemical messengers within the body [3]. The human body needs different types of beneficial fats to ensure its systems function properly. Maintaining a balance of lipid concentrations in the blood is crucial for overall health [4].
Lipid metabolism is essential for various vital functions, including energy storage, hormone regulation, neurotransmission, and the transport of fat-soluble nutrients. Lipids serve as a highly efficient energy source, providing 9 kcal per gram—much more than proteins and carbohydrates. The body can store up to 100,000 kcal of energy as lipids, enabling survival without food for 30–40 days with adequate water intake [5]. These biochemical lipids are stored mainly in cells, especially in adipose tissue, a type of connective tissue. They protect vital organs like the spleen, liver, heart, and kidneys by cushioning them from damage. Lipids in the blood are absorbed by liver cells, which distribute them to various parts of the body in appropriate amounts. The liver plays a central role in lipid metabolism, acting as a secondary storage reservoir for excess fats. When energy intake exceeds expenditure, the surplus is stored as triglycerides in adipose tissue and hepatocytes. The metabolic cycle also involves the citric acid cycle, the urea cycle, and the Krebs cycle [6]. Lipid metabolism plays a vital role in various cellular processes crucial for maintaining homeostasis, such as the synthesis of membranes and storing energy in the form of triglycerides (TG) [7]. Fatty acids (FAs) are vital lipids that make up the primary structural elements of membrane lipids, including glycerophospholipids (GPLs) and sphingolipids. Additionally, they serve as a key energy source through processes like mitochondria-mediated beta-oxidation and the tricarboxylic acid (TCA) cycle, also known as the citric acid cycle [8].
The classification of specific lipid metabolic disorders depends on the levels of various groups of lipoproteins. Many disorders are identifiable by structural defects, irrespective of the presence or absence of apolipoproteins and lipid transfer proteins [9]. Lipid metabolism issues or abnormalities can lead to a range of disorders and diseases. Excessive lipid storage in the body can result in conditions like xanthoma, Bassen-Kornzweig syndrome, chylomicronemia syndrome, familial lipoprotein lipase deficiency, Niemann-Pick disease (types A and B), methylmalonic acidemia, GM1 and GM2 gangliosidoses, and Gaucher disease. More serious consequences include cardiovascular disorders and diabetes, which often develop without noticeable symptoms. In today’s digital age, these have become major health concerns. The leading causes of acquired hyperlipidemia include diabetes mellitus, alcohol consumption, hypothyroidism, renal failure, and the prolonged use of diuretics and beta-blockers [10]. Variations in lipid levels can lead to lipid disorders, often characterized by elevated triglycerides or LDL (low-density lipoprotein), or both. The body relies on beneficial fatty acids like HDL (high-density lipoprotein) to remove bad cholesterol. Conversely, the buildup of harmful lipids such as LDL and triglycerides can damage arteries and increase cardiovascular risk. A recent study by Xiao et al. (2021) identified over 80 diseases associated with complex lipid metabolism defects [11], examining their role in health disorders, including nonlysosomal sphingolipids and acylceramides. Fredrickson’s classification divides lipid metabolism disorders into five types based on their pathways and health effects [12]. High amounts of circulating lipids have been associated with metabolic disorders and cancer. In metabolic disorders, an imbalance between the synthesis and expenditure of fatty acids (FAs) leads to the accumulation of lipid metabolites within cells. This build-up can cause dysfunctional cells and death in various tissues, involving the kidneys, brain, skeletal muscles, and heart [13].
As we age, body fat increases, accompanied by changes in lipid metabolism and metabolite levels. Surplus adiposity and amplified lipotoxicity contribute to many age-related diseases, such as cardiovascular disease, cancer, arthritis [14], type 2 diabetes, and Alzheimer’s disease [15]. Mechanistically, oxysterol stress can drive chondrocyte death via p53–Akt–mTOR signaling [16]. The complications of lipid metabolism create challenges to pinpoint its specific mechanisms and roles during aging. However, advances in genetic engineering techniques have shown that changes in lipid metabolism are linked to aging and related diseases. This review explores the latest progress in our understanding of lipid metabolism in aging, including conventional findings and new advances [17]. The objective of this review is to synthesize how core lipid pathways and lipid-derived signals intersect with metabolic disease and aging. We first outline lipid synthesis, storage, mobilization, and oxidation, then summarize enzymatic, hormonal, and transcriptional regulation. We next discuss how lipid-derived signaling integrates with these pathways, how their disruption contributes to cardiometabolic and neurodegenerative disorders, and how aging reshapes these interactions. Finally, we propose a pathway-to-phenotype framework that connects specific lipid signatures with therapeutic targets, spanning pharmacologic agents and lifestyle interventions across the lifespan.
In this review, fatty acid synthesis refers specifically to ACC–FASN–mediated chain elongation to palmitate, whereas lipogenesis denotes the broader process encompassing de novo fatty acid synthesis, triglyceride and phospholipid assembly, and cholesterol biosynthesis; lipolysis denotes hydrolysis of stored triglycerides to fatty acids and glycerol; β–oxidation refers to mitochondrial and peroxisomal fatty acid catabolism to acetyl–CoA for energy. Compared with existing reviews that separately address lipid metabolism, lipid signaling, or aging, we focus on their convergence into defined lipid lesions that can be mapped onto clinical phenotypes and therapeutic targets. This pathway-to-phenotype view emphasizes age-sensitive, tissue- and species-resolved interpretation of lipid data and is intended to guide mechanism-based intervention design.
2. Lipid Pathways: Synthesis, Storage, Mobilization, and Oxidation
The FAs play multiple critical roles in the body: they act as building blocks in cells, serve as central biochemical intermediates, influence membrane properties, modulate cellular signaling pathways, and provide a vital fuel source [18]. All lipids are water-insoluble; they can be broadly labelled as FAs, phospholipids, or neutral lipids (such as TGs and cholesteryl esters) [10]. FAs, the fundamental building blocks of all lipids, serve as precursors for the synthesis of more lipids, including glycerolipids, glycerophospholipids (GPLs), sphingolipids, sterols, and saccharolipids [19]. The biological roles of various lipid groups are determined by their lipid head groups. An imbalance between fatty acid absorption and oxidation can result in the buildup of long-chain fatty acids, which are subsequently incorporated into triglycerides, phospholipids, and other lipid species. Specific lipids, like ceramides, diacylglycerols (DAGs), and acyl-carnitines, are known to regulate intracellular signaling pathways and metabolism, but they are also considered toxic signaling lipid species [13].
2.1. Fatty Acid Synthesis
This process primarily occurs in the cytosol of hepatocytes and adipocytes, with elongation/desaturation in ER. Fatty acid production is an anabolic process that generates various lipid species. The enzyme fatty acid synthase (FASN) plays a key role in this process, altering dietary carbohydrates into long-chain saturated fatty acids, primarily generating the 16-carbon fatty acid palmitate. This conversion employs acetyl-CoA (Ac-CoA) as the primary building block. FASN is critical for supplying the required lipids that support the structure of cellular membranes and facilitate intracellular signaling. It begins with ATP citrate lyase (ACLY), an enzyme that converts citrate from the citric acid cycle (TCA) into Ac-CoA in the cytoplasm, which then acts as a precursor for fatty acid synthesis. Mitochondrial Ac–CoA cannot traverse the inner membrane. Because Ac–CoA cannot cross the mitochondrial inner membrane, citrate is exported via SLC25A1 and cleaved by ACLY to generate cytosolic Ac–CoA for fatty acid and cholesterol synthesis, with ACSS2 providing an acetate–to–Ac–CoA salvage route in cytosol. This complex metabolic pathway underlines the importance of lipid production in regulating cellular integrity and function [20]. In the process of fatty acid synthesis, FASN sequentially adds seven malonyl-CoA molecules to a single acetyl-CoA, producing palmitate, a 16-carbon saturated fatty acid. Once made, palmitate undergoes activation by acyl-CoA synthetase (ACS), which prepares it for further modification. The activated fatty acid can then be elongated by fatty acid elongase 5 (ELOVL5) and desaturated by enzymes like stearoyl-CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2), providing a series of fatty acid molecules with distinct chain lengths and saturation degrees [21]. Synthesized fats are deposited in cells as TGs. Diglyceride acyltransferase (DGAT) performs a key role in the TG synthesis pathway by transforming DAG into triglycerides (TAGs) [22].
The enzymes participating in fatty acid synthesis are controlled at the transcriptional stage by sterol regulatory element-binding protein 1 (SREBP-1) transcription factors. Lately, a genome-wide CRISPR screen was conducted to systematically map genetic interactions (GIs) in human HAP1 cells (a near-haploid human cell line resulting from chronic myelogenous leukemia [CML]). This work aimed to explore how cells adapt to the loss of de novo FA synthesis [23].
2.2. Lipolysis
Adipose and liver lipid droplets are the primary sites and intracellular lipases act at the LD surface. Triglycerides serve as a proficient and inert form of FAs for storing and transporting, but they cannot cross cell membranes directly. Therefore, TGs must either be broken down into FAs and glycerol through hydrolysis or transported across cell membranes via specialized vesicles. This transport involves the secretion and uptake of TG-rich lipoproteins or the movement of TGs by extracellular vehicles (EVs). The breakdown of TGs, known as lipolysis, is catalyzed by lipases [24].
The function of neutral lipid metabolism in cellular signaling has gained significant attention, especially with the discovery that elevated TG levels in cells are closely linked to insulin resistance in muscle tissue and the liver [25]. However, the moderately inert nature of TGs suggests they do not directly interfere with insulin signaling. This idea is supported by the “athletes’ paradox”, where endurance athletes have higher TG accumulation in the lipid droplets (LDs) of their skeletal muscle cells yet remain highly insulin sensitive [26]. Similarly, mice lacking adipose triglyceride lipase (ATGL) accumulate large fractions of fat in several tissues, including skeletal muscle, heart muscle, liver, kidneys, and macrophages, but show increased insulin sensitivity. This increased sensitivity occurs despite ATGL deficiency, leading to an insulin-secretion defect in pancreatic islets [27].
At lipid droplets, ATGL activation via CGI–58 and PKA-phosphorylated HSL are coordinated by perilipins, while insulin restrains lipolysis through PDE3B-mediated dampening of PKA signaling. The G0S2 tonically inhibits ATGL, establishing a hormonal and protein–scaffold gate on FA release. Additionally, FAs actively contribute to cellular signaling pathways and the regulation of gene transcription. FAs or their products can bind to and activate nuclear receptors, a family of transcription factors that regulate genes responsible for energy homeostasis and inflammation. Among these, the peroxisome proliferator-activated receptors (PPARs) are the most explored. The PPAR family includes four members: PPARα, PPARγ-1, PPARγ-2, and PPARδ (also known as PPARβ). PPARα and PPARδ are abundantly expressed in oxidative tissues and control genes included in substrate delivery, substrate oxidation, and oxidative phosphorylation (OXPHOS). In contrast, PPARγ plays a key role in lipogenesis and lipid synthesis, with the highest expression levels found in white adipose tissue (WAT) [28].
According to recent advances, PPARs pose as complex therapeutic paradoxes that cause failures in clinical translational research. Studies show that PPARδ acts as a transcriptional repressor via direct RelA (p65) binding, leading to suppression of cytotoxic T lymphocyte functions, which may cause acceleration of cancer progression [29]. From a clinical perspective, mono-targeted PPAR advances have shown a critical gap in translation. For example, PPARα agonists, also known as fibrates, have actively failed in showing positive clinical results for metabolic liver disease treatment, despite their functional roles in lipid metabolism [30,31,32].
Elevated cellular levels of non-esterified fatty acids (FAs), especially palmitate, can lead to the production of lipotoxic lipids like ceramides, which disrupt effective insulin signaling. Furthermore, FAs can increase the formation of reactive oxygen species, which then activate redox-sensitive serine kinases. These kinases, in turn, impair insulin activity [33].
2.3. Lipogenesis
In humans, lipogenesis occurs in adipocytes and hepatocytes with organelle partitioning between cytosol and ER. The hepatic de novo lipogenesis can be quantitatively important in steatotic states even if adipose fat mass accrues largely from FA uptake. Most cells have the ability to transform carbohydrates into fatty acids, which are often stored as neutral lipids within lipid droplets. Increasing studies indicate that lipogenesis is important not only in metabolic tissues for maintaining overall energy balance but also in the immune and nervous systems for their growth, differentiation, and even in their pathological functions. Consequently, both excessive and insufficient lipogenesis are closely linked to disruptions in lipid homeostasis, potentially leading to conditions such as dyslipidemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative disorders, and cancers. To ensure systemic energy balance, the enzymes involved in lipogenesis are tightly regulated through transcriptional and post-translational modifications [34]. Cytosolic acetyl–CoA for fatty acid and cholesterol synthesis derives from citrate exported by SLC25A1 and cleaved by ATP–citrate lyase (ACLY), positioning ACLY as a nodal enzyme between mitochondrial metabolism and lipogenesis. ACC carboxylates acetyl–CoA to malonyl–CoA, supplying FASN and constraining β-oxidation via CPT1 inhibition. On the other hand, SREBP–2 preferentially controls the cholesterol arm (e.g., HMG–CoA reductase) alongside SREBP–1 control of fatty acid genes. Citrate is exported via SLC25A1 and cleaved by ACLY to produce cytosolic acetyl–CoA for fatty acid and cholesterol synthesis, with acetate salvage via ACSS2 (Acyl–CoA synthetase short–chain family member 2) as an auxiliary source.
In rats, lipogenesis primarily takes place in the liver and WAT, while in humans, it plays a minor role in overall fat balance. Lipid accumulation in adipose tissue largely depends on the uptake of circulating FAs. These FAs are released through the enzymatic breakdown of TG in chylomicrons by lipoprotein lipase. Once FAs enter the adipocyte, they must be re-esterified for storage in the form of TG. Several enzymes involved in adipose tissue lipogenesis, such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and malic enzyme (ME), are induced by insulin. Newly synthesized FAs are then utilized as substrates for TG synthesis. The insulin-mediated stimulation of lipogenesis in response to nutritional status results from increased enzyme activities implicated in FA biosynthesis and elevated gene expression of these enzymes [35]. In skeletal muscle, de novo lipogenesis and re-esterification can operate alongside fatty acid oxidation. And this is known to generate a ‘futile’ lipid cycle that dissipates energy and buffers lipid intermediates, particularly under chronic stress or denervation-associated catabolism [36,37,38]. This cycling is heightened when substrate influx and oxidative demand are simultaneously elevated. This is observed in neuromuscular disease models. Emerging data indicate that neuronal metabolites such as N-acetylaspartate (NAA) can contribute acetate equivalents to peripheral acetyl-CoA pools via aspartoacylase and acetyl-CoA synthetase, potentially augmenting myocellular lipogenesis and re-esterification under high turnover states, thereby intensifying futile lipid cycling in disease contexts [39,40].
2.4. β-Oxidation
Mitochondria are the primary site in oxidative tissues and peroxisomes for the very-long-chain substrates in our body. Long-chain fatty acids are initially activated by acyl-CoA synthetases and transported into mitochondria by the carnitine shuttle (CPT1/CACT/CPT2). On the other hand, very-long-chain species undergo initial peroxisomal chain–shortening before mitochondrial oxidation, with tissue differences in flux partitioning across liver, heart, and skeletal muscle. CPT1 isoforms integrate malonyl–CoA inhibition, coupling β-oxidation to lipogenesis state, while glucagon–PKA signaling lowers malonyl–CoA and promotes oxidation via CPT1 induction, establishing a hormonal gate at the mitochondrion. Further dehydrogenation, hydration, and thiolysis produce acetyl-CoA for the tricarboxylic acid cycle [41]. Although skeletal muscle and cardiac oxidation play a key role in regulating energy homeostasis under aerobic conditions, adipose-specific loss does not affect full-body insulin sensitivity. Moreover, tissue-specific knockout models of carnitine palmitoyl transferase 2 indicate that organs act differently for metabolic functions [42].
Pathway-to-tissue mapping helps in clarifying the phenotypes. Like, adipose lipolysis controls FA delivery and the hepatic de novo lipogenesis determines VLDL output. Additionally, cardiac/skeletal mitochondrial β-oxidation is known to govern the fasting endurance, while peroxisomal oxidation safeguards against very-long-chain lipid toxicity.
8. Discussion
Alterations in lipid metabolism are also linked to critical features of aging, including epigenetics. These findings indicate that lipid metabolism is a major player in biological processes, contributing significantly to aging and age-related diseases. Although current evidence suggests a connection between lipid metabolism and longevity, more research is needed to address remaining questions. In the future, studies should focus on understanding how lipid-related interventions can extend lifespan, particularly using vertebrate models to validate findings from non-vertebrate organisms like C. elegans. This review offers a comprehensive overview of the complex roles of lipid metabolism and signaling in health, aging, and metabolic diseases. We explored how closely regulated lipid pathways ensure energy homeostasis and signal cascades, while disruptions contribute to a spectrum of disorders comprising obesity, cardiovascular disease, and neurodegeneration. The convergence of lipid metabolic and signaling pathways in response to stress, aging, and disease strengthens their integrative biological impact. Essentially, this review highlights the age-related decline in lipid metabolic efficiency, described by modulated lipogenesis, impaired lipid clearance, and changes in lipid storage and signaling dynamics. These age-related alterations are associated with increased susceptibility to chronic metabolic disorders, indicating lipid dysfunction as both a driver and a biomarker of aging.
From a therapeutic perspective, recent advances feature the potential of targeting specific enzymes and receptors implicated in lipid pathways. Pharmacological interventions, such as FASN, ACC, and MAGL inhibitors, are being actively studied, while lifestyle strategies—mainly customized diets and physical activity—offer scalable and non-invasive options to mitigate lipid-associated risks. Nonetheless, the translation of these findings into clinical practice remains challenging due to the complexity of lipid signaling, systemic variability, and context-dependent outcomes. Future research should focus on integrating lipidomics with genomics and transcriptomics to unravel individualized lipid profiles and therapeutic susceptibilities. Multidisciplinary interventions, including systems biology, precision nutrition, and molecular pharmacology, are crucial for developing targeted approaches that address the root causes of lipid-driven diseases.
9. Conclusions
Lipid metabolism and signaling are fundamental to the regulation of cellular homeostasis, energy balance, and systemic physiological functions. This review has demonstrated the multifunctional roles of lipids, not only as structural and energetic components but also as dynamic signaling molecules that network with major pathways such as insulin signaling, mTOR, PPARs, and AMPK. These interactions are specifically significant in the framework of metabolic disorders where aberrant lipid accumulation, chronic inflammation, and altered lipid signaling contribute to disease pathogenesis.
The interaction between lipid metabolism and lipid-mediated signaling becomes increasingly complex with aging. Age-related impairments in lipid turnover, mitochondrial function, and signal transduction exacerbate receptiveness to insulin resistance, cardiovascular disease, and neurodegenerative conditions. Furthermore, changes in lipid composition and distribution during aging damage membrane integrity and receptor function, amplifying metabolic disruption. Therapeutically, targeting enzymes like ACC, FASN, and lipid-sensitive receptors such as PPARs or GPCRs provides promising avenues for metabolic intervention. Advances in lipidomics, transcriptomics, and pharmacogenomics are paving the way for precision medicine options that can stratify patient populations based on lipid signatures and individual responses to treatment. Lifestyle modifications, including caloric restriction, tailored diets, and exercise, remain necessary adjunct strategies that can synergistically improve lipid profiles and signaling outcomes. Therefore, a systemic knowledge of lipid metabolism and signaling is important for deciphering the pathophysiology of metabolic diseases and age-associated impairments. Continued research into the regulatory interactions and molecular targets within these lipid pathways will not only deepen our biological understanding but also unlock novel therapeutic strategies to deal with the growing global burden of metabolic disorders. Key unresolved questions include how to causally link specific lipid species and spatially resolved lipid niches to defined clinical phenotypes, how to safely manipulate central lipid enzymes in multimorbid and older patients, and how to embed lipidomic profiling into routine care. Addressing these gaps will enable mechanism-based prevention and treatment strategies that align lipid signatures, organ involvement, and therapeutic intensity, and will improve risk stratification in obesity- and age-associated metabolic disease.
Acknowledgments
S.G. and J.K.S. acknowledge the support from GloNeuro and the International Brain Research Organization (IBRO).
Data Availability Statement
No new data were created or analyzed in this study.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript: ACCAcetyl-CoA carboxylaseACSS2Acyl–CoA synthetase short–chain family member 2ACLYATP-citrate lyaseACS/ACSLAcyl-CoA synthetase/Acyl-CoA synthetase long-chainAMPKAMP-activated protein kinaseAETAerobic exercise trainingALAα-Linolenic acidApoA-IApolipoprotein A-IApoC-IIApolipoprotein C-IIATGLAdipose triglyceride lipaseCIC/SLC25A1Mitochondrial citrate carrierCPT-1Carnitine palmitoyltransferase 1cAMPCyclic adenosine monophosphateCREBcAMP response element-binding proteinDAGDiacylglycerolDNLDe novo lipogenesisDGATDiacylglycerol acyltransferaseFAFatty acidFAOFatty acid oxidationFASN/FASFatty acid synthaseFFAFree fatty acidFXRFarnesoid X receptorGPLGlycerophospholipidHDLHigh-density lipoproteinHFDHigh-fat dietHSCHematopoietic stem cellIGF-1Insulin-like growth factor 1IISInsulin/IGF-1 signalingIP3Inositol trisphosphateIRSInsulin receptor substrateJNKc-Jun N-terminal kinaseKGDHC(Not used—ignore)Krebs cycle/TCATricarboxylic acid cycleLD/LDsLipid droplet(s)LDLLow-density lipoproteinLPLLipoprotein lipaseMEMalic enzymeMETMetabolic equivalent of taskmTOR/mTORC1/mTORC2Mechanistic target of rapamycin (complex 1/2)MUFAsMonounsaturated fatty acidsNAEsN-acylethanolamides (e.g., anandamide)NAFLDNon-alcoholic fatty liver diseaseNASHNon-alcoholic steatohepatitisNPC1L1Niemann–Pick C1-like 1OXPHOSOxidative phosphorylationPA/PPLPhysical activity/Postprandial lipemiaPCSK9Proprotein convertase subtilisin/kexin type 9PDK1Pyruvate dehydrogenase kinase 1PFAParaformaldehyde (in immunohistochemistry, if used)PIP2/PIP3Phosphatidylinositol-4,5-bisphosphate/Phosphatidylinositol-3,4,5-trisphosphatePLIN1/2/5PerilipinsPPAR (α, γ-1, γ-2, δ)Peroxisome proliferator-activated receptorSCAPSREBP cleavage-activating proteinSCDStearoyl-CoA desaturaseSCFAShort-chain fatty acidSFASaturated fatty acidSREBPsSterol regulatory element-binding proteinsTGTriglycerideTVB-2640Denifanstat (Fatty acid synthase inhibitor)TCATricarboxylic acid cycleVLCFAVery-long-chain fatty acidVLDLVery low-density lipoproteinWATWhite adipose tissue
| Category | Disorder Name | Primary Lipid Involved | Key Enzyme/Protein Affected | Clinical Manifestations |
|---|---|---|---|---|
| Hyperlipidemias [64] | Familial Hypercholesterolemia | Cholesterol | LDL Receptor | Premature atherosclerosis, xanthomas |
| Familial Combined Hyperlipidemia | Cholesterol, Triglycerides | Multiple genes involved | Elevated LDL and triglycerides, risk of CHD | |
| Hypertriglyceridemia | Triglycerides | LPL or ApoC-II deficiency | Pancreatitis, xanthomas, hepatosplenomegaly | |
| Hypolipidemias [65] | Abetalipoproteinemia | Cholesterol, Triglycerides | Microsomal triglyceride transfer protein (MTTP) | Fat malabsorption, retinal degeneration, neuropathy |
| Hypoalphalipoproteinemia | HDL | ApoA-I deficiency | Low HDL levels, increased risk of atherosclerosis | |
| Lysosomal Storage Disorders [66] | Gaucher Disease | Glucosylceramide | Glucocerebrosidase | Hepatosplenomegaly, bone crises, neurological symptoms |
| Niemann-Pick Disease | Sphingomyelin, Cholesterol | Sphingomyelinase (Types A, B) | Hepatosplenomegaly, neurodegeneration | |
| Peroxisomal Disorders [67] | Zellweger Syndrome | Very-long-chain fatty acids | Peroxisome biogenesis | Craniofacial dysmorphism, liver dysfunction |
| Fatty Acid Oxidation Disorders [68] | Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) | Medium-chain fatty acids | Medium-chain acyl-CoA dehydrogenase | Hypoglycemia, lethargy, liver dysfunction |
| Cholesterol Metabolism Disorders [69] | Smith-Lemli-Opitz Syndrome | Cholesterol | 7-Dehydrocholesterol reductase | Developmental delay, dysmorphic features |
| Sitosterolemia | Plant sterols | ABCG5/ABCG8 | Tendon xanthomas, premature atherosclerosis |