Fats

Digestion and absorption

In the small intestine, enzymes from the pancreas split fat into fatty acids and monoacylglycerol, which the gut lining rebuilds into fat ¹².

Pancreatic lipase prefers the sn-1 and sn-3 esters of triacylglycerol; colipase anchors it to the lipid–water interface against displacement by bile salts ². In enterocytes, MGAT2 and DGAT1, both highly expressed in the intestine, resynthesise triacylglycerol ³.

Monoacylglycerol pathway of dietary fat absorptionIntestinal lumen, then endoplasmic reticulum of enterocytes

Triacylglycerol (lumen)
Pancreatic lipase (PNLIP)Colipase (CLPS), 2 H2OCleaves sn-1 and sn-3 esters; releases two fatty acids
sn-2-Monoacylglycerol
Monoacylglycerol O-acyltransferase 2 (MOGAT2)Fatty acyl-CoAEnterocyte ER; over 75% of postprandial intestinal TAG synthesis
Diacylglycerol
Diacylglycerol O-acyltransferase 1 (DGAT1)Fatty acyl-CoAOnly DGAT detected in human intestine
Triacylglycerol (enterocyte)
several stepsAssembly requires APOB and microsomal triglyceride transfer protein (MTTP)
Chylomicron

Lipoproteins

Fat does not dissolve in blood, so it travels in lipoproteins, particles of fat coated with phospholipid, cholesterol and proteins ¹.

Enterocytes secrete chylomicrons into lymph, one apoB-48 per particle; the liver secretes VLDL, one apoB-100 per particle ¹. Lipoprotein lipase, anchored to capillary endothelium by GPIHBP1, hydrolyses their triacylglycerol; apoC-II activates it and apoC-III inhibits it ¹⁴. Loss-of-function variants in LPL, APOC2, GPIHBP1, LMF1 or APOA5 can cause familial chylomicronaemia syndrome ¹.

The liver takes up chylomicron remnants and about half of VLDL remnants through apoE; hepatic lipase converts the rest to LDL ¹. Hepatic LDL receptors clear about 70% of LDL, and statins increase their number ¹. HDL forms as ABCA1 loads apoA-I with cholesterol and phospholipid, and LCAT esterifies that cholesterol ¹; see cholesterol.

Carnitine shuttle and β-oxidation

Cells burn fatty acids inside mitochondria, two carbon atoms at a time ⁵.

CPT1 on the outer mitochondrial membrane transfers long-chain acyl groups from CoA to carnitine; SLC25A20 carries acylcarnitine into the matrix, and CPT2 restores acyl-CoA there ⁵. In each turn of β-oxidation, the acyl-CoA is dehydrogenated with FAD, hydrated, dehydrogenated with NAD+ and cleaved with CoA, releasing acetyl-CoA; palmitoyl-CoA takes seven turns ⁵.

Carnitine shuttle and β-oxidation of palmitateCytosol, outer and inner mitochondrial membranes, mitochondrial matrix

Palmitate (16:0)
Long-chain-fatty-acid–CoA ligase 1 (ACSL1)ATP, CoA, Mg2+Outer mitochondrial membrane and ER; releases AMP and diphosphate
Palmitoyl-CoA
Carnitine palmitoyltransferase 1 (CPT1A, CPT1B)L-CarnitineMalonyl-CoAOuter mitochondrial membrane; CPT1A in liver, CPT1B in muscle; releases CoA
Palmitoylcarnitine
Carnitine–acylcarnitine translocase (SLC25A20)Inner membrane; exchanges acylcarnitine for free carnitine
Palmitoylcarnitine (matrix)
Carnitine palmitoyltransferase 2 (CPT2)CoAMatrix side of the inner membrane; releases carnitine
Palmitoyl-CoA (matrix)
Very-long-chain acyl-CoA dehydrogenase (ACADVL)FADReduces ETF; ETF–ubiquinone oxidoreductase passes electrons to ubiquinone
trans-Hexadec-2-enoyl-CoA
Trifunctional protein α subunit (HADHA)H2OEnoyl-CoA hydratase activity
(S)-3-Hydroxyhexadecanoyl-CoA
Trifunctional protein α subunit (HADHA)NAD+Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity
3-Oxohexadecanoyl-CoA
Trifunctional protein β subunit (HADHB)CoA3-Ketoacyl-CoA thiolase activity; releases acetyl-CoA
Myristoyl-CoA (14:0)
several stepsSix more turns; palmitoyl-CoA yields 8 acetyl-CoA, 7 FADH2 and 7 NADH
Acetyl-CoA

CPT1A deficiency causes hypoketotic hypoglycaemia after fasting; myopathic CPT2 deficiency causes myoglobinuria with prolonged exercise or fasting ⁴.

Fatty acid synthesis and malonyl-CoA

The liver and fat tissue can make fatty acids from carbohydrate ⁵.

Mitochondrial acetyl-CoA reaches the cytosol as citrate, which ATP-citrate lyase cleaves ⁵. Acetyl-CoA carboxylase, a biotin enzyme activated by citrate and inactivated by AMPK phosphorylation, forms malonyl-CoA ⁴. Fatty acid synthase joins one acetyl-CoA and seven malonyl-CoA into palmitate, using 14 NADPH ⁵. Unlike β-oxidation, synthesis is cytosolic, uses an acyl-carrier domain and NADPH, and passes through (3R)- instead of (3S)-hydroxyacyl intermediates ⁴.

Synthesis of oleic acidCytosol, then endoplasmic reticulum membrane

Acetyl-CoA
Acetyl-CoA carboxylase 1 (ACACA)ATP, HCO3−, BiotinFirst and rate-limiting step of de novo fatty acid synthesis
Malonyl-CoA
Fatty acid synthase (FASN)Acetyl-CoA, 14 NADPH7 malonyl-CoA per palmitate; releases 7 CO2; thioesterase domain frees 16:0
Palmitate (16:0)
Long-chain-fatty-acid–CoA ligases (ACSL)ATP, CoA, Mg2+Releases AMP and diphosphate
Palmitoyl-CoA
several stepsMalonyl-CoA, 2 NADPHElongation cycle: ELOVL6, HSD17B12, HACD, TECR; releases CO2
Stearoyl-CoA (18:0)
Stearoyl-CoA desaturase (SCD)O2, 2 reduced cytochrome b5NADH-cytochrome b5 reductase (CYB5R3) supplies the electrons
Oleoyl-CoA (18:1 cis-Δ9)

Malonyl-CoA also inhibits CPT1, which limits simultaneous synthesis and oxidation ⁵⁶. In rat liver homogenates, McGarry and colleagues found in 1977 that malonyl-CoA inhibited ketogenesis from oleate but not from octanoate, which needs no carnitine ⁷. In young men, fructose or sucrose drinks for 7 weeks raised hepatic de novo lipogenesis ⁸; see sugar and fructose.

Essential fatty acids

The body cannot make linoleic acid (omega-6) or α-linolenic acid (omega-3), so both must come from food ⁹.

SCD desaturates at Δ9, FADS2 at Δ6 and FADS1 at Δ5; humans lack Δ12- and Δ15-desaturases ²¹⁰⁹. Desaturases and elongases convert linoleic acid to arachidonic acid and α-linolenic acid to EPA, and one peroxisomal β-oxidation cycle completes DHA ¹⁰; see palm and seed oils and fish and omega-3. When linoleic acid is scarce, the same enzymes convert oleic acid to 5,8,11-eicosatrienoic acid ¹¹. In four healthy men infused intravenously for 2 weeks with fat-free glucose and amino acids, linoleic acid fell from 48.8% to 9.8% of plasma cholesteryl-ester fatty acids, and eicosatrienoic acid appeared ¹¹.

References

Textbook or database
Feingold KR. Introduction to Lipids and Lipoproteins Endotext, MDText.com, Inc., South Dartmouth (MA), 2024.
PubMed 26247089
Funding and finding
Funding
This work was supported by grants from the Northern California Institute for Research and Education.
Finding
Textbook chapter, updated 14 January 2024, read in the chapter XML of the NCBI Bookshelf open-access archive of Endotext. Lipids are insoluble in water and travel in lipoproteins, with a core of cholesteryl esters and triglycerides inside a surface of phospholipids, free cholesterol and apolipoproteins. Intestinal lipases hydrolyse dietary triglycerides to fatty acids and monoacylglycerol, which enterocytes resynthesise into triglycerides with MGAT and DGAT. Each chylomicron, made by the intestine, carries one apoB-48; each VLDL, made by the liver, and each IDL and LDL particle carries one apoB-100. MTTP transfers triglycerides to apoB-100 in the liver and to apoB-48 in the intestine; its absence prevents chylomicron formation (abetalipoproteinaemia). Chylomicrons are secreted into lymph and reach the systemic circulation through the thoracic duct. Triglyceride availability is the primary determinant of VLDL secretion. LPL, synthesised in muscle, heart and adipose tissue, is anchored to capillary endothelium by GPIHBP1 and hydrolyses the triglycerides of chylomicrons and VLDL; apoC-II is its cofactor, and apoC-III inhibits it. Loss-of-function mutations in LPL, APOC2, GPIHBP1, LMF1 and APOA5 can cause familial chylomicronaemia syndrome. The liver clears chylomicron remnants through apoE binding to the LDL receptor, LRP and syndecan-4, and clears about 50% (variable) of IDL; hepatic lipase hydrolyses the triglycerides of the remaining IDL, forming LDL. About 70% of circulating LDL is cleared by hepatocyte LDL receptors; statins, ezetimibe, PCSK9 inhibitors, bile acid sequestrants and bempedoic acid lower plasma LDL by increasing hepatic LDL receptors. Nascent HDL forms when ABCA1 effluxes cholesterol and phospholipids to lipid-poor apoA-I; LCAT, activated by apoA-I, esterifies HDL cholesterol. The pathway of fatty acid absorption is not well understood: humans and mice deficient in CD36 do not have fat malabsorption, mice deficient in FATP4 have no abnormality of fat absorption, and the pathways of monoacylglycerol uptake remain to be defined. The precise pathway of VLDL secretion from hepatocytes is not resolved.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA); National Institute of General Medical Sciences (NIGMS) [R35GM141873]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Eye Institute (NEI); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 - Research and Innovation Framework Programme [825575]; State Secretariat for Education, Research and Innovation (SERI); European Molecular Biology Laboratory (EMBL) Australia. Funding for open access charge: National Institutes of Health.
Finding
Reviewed human entries read 2026-10-21. PNLIP (P16233) preferentially splits the esters of long-chain fatty acids at positions 1 and 3, producing mainly 2-monoacylglycerol and free fatty acids. CLPS (P04118) is a cofactor that anchors pancreatic lipase at the lipid-water interface; without it bile salts wash the enzyme off. MOGAT2 (Q3SYC2) transfers an acyl chain from acyl-CoA to monoacylglycerol, forming diacylglycerol. DGAT1 (O75907) catalyses the terminal and only committed step of triacylglycerol synthesis, is highly expressed in small-intestinal epithelial cells and is essential for absorption of dietary fats. MTTP (P55157) transports triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces and is required for assembly and secretion of apolipoprotein B-containing lipoproteins. APOB (P04114): apo B-48 is a major protein of chylomicrons. SCD (O00767) inserts a cis double bond at the delta-9 position of fatty acyl-CoA substrates including stearoyl-CoA, using O2 and electrons from reduced cytochrome b5. FDFT1 (P37268) condenses two farnesyl diphosphates to squalene, the first committed step of sterol biosynthesis. SQLE (Q14534) oxidises squalene to (S)-2,3-epoxysqualene and is considered rate-limiting in steroid biosynthesis. COMT (P21964) catalyses catechol + S-adenosyl-L-methionine = guaiacol + S-adenosyl-L-homocysteine; the Val158Met variant results in a 3- to 4-fold difference in activity. LCT (P09848), lactase/phlorizin hydrolase, a homodimer of the apical membrane of small-intestinal enterocytes, hydrolyses lactose to beta-D-galactose and D-glucose (EC 3.2.1.108). SLC5A1 (P13866, SGLT1) transports D-glucose or D-galactose across the apical membrane of enterocytes with 2 Na+ per sugar; basolateral exit is provided by GLUT2. SLC2A2 (P11168, GLUT2) is a facilitative transporter of glucose, fructose and galactose. GALM (Q96C23), GALK1 (P51570), GALT (P07902) and GALE (Q14376) constitute the Leloir pathway that converts beta-D-galactose to glucose 1-phosphate in the liver; GALM interconverts beta- and alpha-D-galactose, GALK1 phosphorylates alpha-D-galactose with ATP in the first committed step, GALT converts alpha-D-galactose 1-phosphate and UDP-glucose to alpha-D-glucose 1-phosphate and UDP-galactose, GALE interconverts UDP-glucose and UDP-galactose. PGM1 (P36871) isomerises alpha-D-glucose 1-phosphate to alpha-D-glucose 6-phosphate via glucose 1,6-bisphosphate. TRPV6 (Q9H1D0) is a calcium-selective channel that mediates Ca2+ uptake in tissues including the intestine. S100G (P29377) is calbindin-D9k, the intestinal vitamin D-dependent calcium-binding protein. ATP2B1 (P20020, PMCA1) transports calcium from the cytoplasm to the extracellular space, is located in the basolateral membrane and promotes intestinal calcium absorption.
Independent research
Yen CE, Nelson DW, Yen MI. Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism Journal of Lipid Research, 2015.
doi:10.1194/jlr.R052902 PubMed 25231105
Funding and finding
Funding
This work was funded by the National Institutes of Health Grant DK088210 and US Department of Agriculture Grant WIS01442.
Finding
Narrative review. Triacylglycerol forms the bulk of animal fats and plant oils and accounts for approximately 95% of dietary fat. Pancreatic lipase prefers sn-1 and sn-3 ester bonds and yields fatty acids and sn-2 monoacylglycerol. In enterocytes the monoacylglycerol pathway, with MGAT2 and DGAT1 in the endoplasmic reticulum, accounts for more than 75% of postprandial intestinal triacylglycerol synthesis; DGAT1 is the only DGAT detected in human intestine. Triacylglycerol forms the core of ApoB-containing chylomicrons, whose assembly requires MTP.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA); National Institute of General Medical Sciences (NIGMS) [R35GM141873]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Eye Institute (NEI); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 - Research and Innovation Framework Programme [825575]; State Secretariat for Education, Research and Innovation (SERI); European Molecular Biology Laboratory (EMBL) Australia. Funding for open access charge: National Institutes of Health.
Finding
Reviewed human UniProtKB entries, release 2026_03, read through rest.uniprot.org on 2026-10-21. CPT1A (P50416), liver isoform: mitochondrial outer membrane, residues 123 to 773 cytoplasmic; transfers the acyl group of long-chain acyl-CoA onto carnitine, an essential step for mitochondrial uptake of long-chain fatty acids; inhibited by malonyl-CoA; CPT1A deficiency causes severe episodes of hypoketotic hypoglycaemia, usually after fasting or illness, from infancy or early childhood. CPT1B (Q92523), muscle isoform: strong expression in heart and skeletal muscle, none in liver and kidney. SLC25A20 (O43772): electroneutral exchange of acylcarnitines for free carnitine across the mitochondrial inner membrane. CPT2 (P23786): inner membrane, matrix side; reconverts acylcarnitines into acyl-CoA; the myopathic, stress-induced form of CPT2 deficiency causes recurrent myoglobinuria and episodes of muscle pain, exacerbated by prolonged exercise, fasting, cold or viral infection. ACSL1 (P33121): long-chain fatty acid + ATP + CoA = long-chain acyl-CoA + AMP + diphosphate, including hexadecanoate; Mg2+; mitochondrial outer membrane, peroxisome and endoplasmic reticulum membranes. ACADVL (P49748): FAD; first reaction of mitochondrial beta-oxidation, dehydrogenating saturated C12 to C24 acyl-CoAs to trans-2-enoyl-CoA with electron-transfer flavoprotein (ETF) as physiological electron acceptor; inner membrane; each cycle shortens the acyl-CoA by two carbons and yields one acetyl-CoA, one FADH2 and one NADH. HADHA (P40939) and HADHB (P55084): heterotetrameric mitochondrial trifunctional enzyme specific for long-chain substrates; the alpha subunit carries the enoyl-CoA hydratase and (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activities, including on (3S)-hydroxyhexadecanoyl-CoA, the beta subunit the 3-ketoacyl-CoA thiolase. ETFA (P13804): accepts electrons from acyl-CoA dehydrogenases and transfers them to the respiratory chain through ETF-ubiquinone oxidoreductase; ETFDH (Q16134): transfers electrons from ETF to ubiquinone, inner membrane. ACLY (P53396): cytosolic; cleaves citrate into oxaloacetate and acetyl-CoA. ACACA (Q13085): cytosolic; carboxylates acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid synthesis; biotin; citrate promotes the most active, filamentous form; phosphorylation at Ser-80 by AMPK inactivates it; inhibited by palmitoyl-CoA. ACACB (O00763): mitochondrial; its malonyl-CoA allosterically inhibits CPT1; activated by citrate; phosphorylation at Ser-222 by AMPK inactivates it. FASN (P49327): cytoplasmic homodimer with 7 catalytic activities and an acyl carrier protein domain; acetyl-CoA + n malonyl-CoA + 2n NADPH = long-chain fatty acid + n CO2; NADPH reduces 3-oxoacyl-[ACP] to (3R)-hydroxyacyl-[ACP]. LPL (P06858): hydrolyses the triglycerides of chylomicrons and VLDL; APOC2 is its coactivator; GPIHBP1 (Q8IV16) anchors it on the luminal surface of capillary endothelium. APOC3 (P02656): inhibits LPL. MTTP (P55157): required for assembly and secretion of apoB-containing lipoproteins; its deficiency causes abetalipoproteinaemia, with virtually no circulating apoB-containing lipoproteins.
Textbook or database
Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. The Reactome Knowledgebase 2026 Nucleic Acids Research, 2026.
doi:10.1093/nar/gkaf1223 PubMed 41251150
Funding and finding
Funding
The development of Reactome is supported by grants from the National Institutes of Health (U24HG012198 and U24HG012198-02S1 for Core Trust Seal development; U24HG011851), European Bioinformatics Institute (EMBL-EBI), Open Targets (The Target Validation Platform), and Connected Minds Prototyping (York University). Funding to pay the Open Access publication charges for this article was provided by the National Institutes of Health (U24HG012198). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Finding
Reactome release 97, pathway and reaction summaries read through reactome.org/ContentService on 2026-10-21. Carnitine shuttle (R-HSA-200425): the malonyl-CoA-sensitive CPT1 of the mitochondrial outer membrane, the carnitine:acylcarnitine translocase SLC25A20 of the inner membrane and CPT2 on the matrix side of the inner membrane transport long-chain fatty acids into the matrix; CPT1A is most abundant in liver and CPT1B in muscle, and malonyl-CoA inhibits both; regulation at ACACA and ACACB minimises simultaneous mitochondrial catabolism and cytosolic biosynthesis of long-chain fatty acids. ACACB, on the outer mitochondrial membrane, regulates fatty acid oxidation through inhibition of CPT1 by its product malonyl-CoA, and phosphorylated AMPK inactivates ACACB in muscle cells (R-HSA-8876889, R-HSA-200423). Mitochondrial fatty acid beta-oxidation (R-HSA-77289): repetitive removal of two-carbon units in four steps, oxidation, hydration, a second oxidation and thiolysis; each turn produces one NADH, one FADH2 and one acetyl-CoA. Beta-oxidation of saturated fatty acids (R-HSA-77286): the first pass for palmitoyl-CoA uses VLCAD (ACADVL) with FAD and the trifunctional protein with H2O, NAD+ and CoA, yielding myristoyl-CoA and acetyl-CoA; later passes use ACADL, ACADM, ACADS, ECHS1 and HADH; the seventh and final pass converts butanoyl-CoA to acetoacetyl-CoA, which yields 2 acetyl-CoA. ATP-citrate synthase (R-HSA-75848): fatty acid synthesis proceeds in the cytosol, while most acetyl-CoA is generated in mitochondria from pyruvate derived from glycolysis and reaches the cytosol as citrate, which ACLY cleaves; ACLY is highly expressed in lipogenic tissues such as liver and white adipose tissue and links carbohydrate metabolism to fatty acid production (R-HSA-9734540). ACACA, a biotin enzyme, is positively regulated by citrate (R-HSA-75851). Fatty acid synthase (R-HSA-75872): acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+ = palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O. Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876): humans lack the desaturases to synthesise polyunsaturated fatty acids from stearate. SLC27A3 (R-HSA-8875077): members of the ACSVL subfamily were first thought to be fatty acid transport proteins (FATPs), but their transport function has never been proven, and their sequences carry two conserved acyl-CoA synthetase motifs.
Independent research
Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics Cell Metabolism, 2017.
doi:10.1016/j.cmet.2016.12.022 PubMed 28178565
Funding and finding
Funding
P.A.C. is supported in part by NIH DK091538.
Finding
Review. Total ketone bodies in healthy adults oscillate between about 100 and 250 µM, rise to about 1 mM after 24 h of fasting or prolonged exercise and reach as high as 20 mM in diabetic ketoacidosis; the human liver produces up to 300 g per day. HMGCS2 catalyses the fate-committing condensation of acetoacetyl-CoA and acetyl-CoA; HMGCL releases acetyl-CoA and acetoacetate; BDH1 interconverts acetoacetate and D-3-hydroxybutyrate in a near-equilibrium NAD+/NADH-coupled reaction; acetoacetate decarboxylates spontaneously to acetone; MCT1 and MCT2 (SLC16A1, SLC16A7) release ketone bodies from cells. SCOT (OXCT1) is expressed in all mammalian cells with mitochondria except hepatocytes and activates acetoacetate without ATP; mitochondrial thiolases (ACAA2, ACAT1, HADHA or HADHB) yield two acetyl-CoA. Heart, skeletal muscle and brain oxidise ketone bodies, including during adherence to low-carbohydrate diets. Acetyl-CoA allosterically activates pyruvate carboxylase; malonyl-CoA inhibits CPT1. Hmgcs2 transcription is stimulated by FOXA2, which insulin inhibits through PI3K and Akt, induced by glucagon-cAMP-p300 signalling and induced by PPAR-alpha and FGF21 in starvation; these shifts have not been linked mechanistically to HMGCS2 protein abundance or ketogenic rate. Loss-of-function HMGCS2 mutations cause bouts of hypoketotic hypoglycaemia.
Independent research
McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis Journal of Clinical Investigation, 1977.
doi:10.1172/JCI108764 PubMed 874089
Funding and finding
Funding
This work was supported by U. S. Public Health Service grant AM-18573 and training grant CA 05200. J. D. McGarry held Research Career Development Award I-KO4-AM0763; G. P. Mannaerts held Fogarty International Fellowship I-FOS-TW223401.
Finding
Malonyl-CoA inhibited ketogenesis from oleic acid but not from octanoic acid; the site of inhibition appeared to be the carnitine acyltransferase I reaction. The effect was specific and easily reversible, and inhibitory concentrations were in the range reported by others in livers of fed rats. The authors proposed that malonyl-CoA is both precursor of fatty acid synthesis and suppressor of fatty acid oxidation.
Independent research
Geidl-Flueck B, Hochuli M, Németh Á, Eberl A, Derron N, Köfeler HC, et al. Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial Journal of Hepatology, 2021.
doi:10.1016/j.jhep.2021.02.027 PubMed 33684506
Funding and finding
Registration
NCT01733563
Participants
126
Follow-up
7 weeks
Funding
This study was funded by the Swiss National Science Foundation (No. 144204), Vontobel Foundation, Rhyner Bangerter Foundation, Promedica Foundation, Uniscientia Foundation, Prof. Otto Beisheim-Foundation, Jubiläumsstiftung Swiss Life, Philhuman Foundation and the Austrian Federal Ministry of Education (No. BMWFW-10.420/0005-WF/V/3c/2017).
In-kind support
Molkerei Biedermann AG provided the beverages in coded containers; the Swiss technology testing service, Dietikon, performed quality control; payment terms are not stated.
Finding
Described as double-blind; the control group abstained from sugar-sweetened beverages and received no placebo. 80 g per day of fructose, sucrose or glucose in three 200 ml beverages for 7 weeks. Median basal hepatic fractional secretion rate of newly synthesised VLDL palmitate (%/day): fructose 19.7 (P=0.013), sucrose 20.8 (P=0.0015), glucose 11.0 (P=0.16), control 9.1. Total energy intake did not change; fasting triglyceride, glucose and insulin did not change; liver fat was not measured.
Regulator
EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol EFSA Journal, 2010.
doi:10.2903/j.efsa.2010.1461
Funding and finding
Funding
European Food Safety Authority, on request from the European Commission (Question No EFSA-Q-2008-466).
Finding
Humans lack delta-12 and delta-15 desaturases, so linoleic acid and alpha-linolenic acid are essential; n-6 and n-3 fatty acids are desaturated and elongated by the same enzymes. Adequate intake 4% of energy for linoleic acid and 0.5% for alpha-linolenic acid. Less than 1% of deuterated linoleic acid was converted to arachidonic acid; alpha-linolenic acid conversion about 8 to 12% to EPA and less than 1% to DHA; conversion of ALA decreases as dietary linoleic acid increases; amounts of n-3 LCPUFA formed depend on ALA intake, not on the n-3/n-6 ratio. Linoleic acid has a negative, dose-dependent relationship with LDL cholesterol. No specific values set for the n-3/n-6 ratio because data on clinical and biochemical endpoints in humans are insufficient to recommend a ratio independent of absolute intakes. No consistent evidence that n-6 PUFA intake has detrimental effects; no upper level set.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute [HG002273]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.
Finding
Reviewed UniProtKB entries, release 2026_03, read through rest.uniprot.org. FADS2 (O95864), acyl-CoA 6-desaturase, endoplasmic reticulum membrane: introduces a cis double bond at carbon 6 and catalyses the first and rate-limiting step of highly unsaturated fatty acid synthesis, the desaturation of linoleoyl-CoA (18:2n-6) and alpha-linolenoyl-CoA (18:3n-3) to gamma-linolenoyl-CoA and stearidonoyl-CoA (18:4n-3), with O2 and 2 Fe(II)-cytochrome b5; in the n-3 series it also desaturates tetracosapentaenoyl-CoA (24:5n-3) to tetracosahexaenoyl-CoA (24:6n-3), which is converted to DHA (by similarity); it carries an N-terminal cytochrome b5 domain and three histidine boxes. FADS1 (O60427), acyl-CoA (8-3)-desaturase: front-end desaturase that introduces a cis double bond at carbon 5 and desaturates dihomo-gamma-linolenoyl-CoA (20:3n-6) and eicosatetraenoyl-CoA (20:4n-3) to arachidonoyl-CoA and eicosapentaenoyl-CoA (20:5n-3). ELOVL5 (Q9NYP7): condensing enzyme of the elongation cycle, its first and rate-limiting reaction, acting on polyunsaturated acyl-CoAs including stearidonoyl-CoA and eicosapentaenoyl-CoA with malonyl-CoA and releasing CO2 and CoA. ELOVL2 (Q9NXB9): condensing enzyme for C20 and C22 polyunsaturated acyl-CoAs, including eicosapentaenoyl-CoA and docosapentaenoyl-CoA (22:5n-3), the latter to 3-oxotetracosapentaenoyl-CoA. HSD17B12 (Q53GQ0, NADPH-dependent 3-ketoacyl-CoA reductase), HACD1 to HACD4 (B0YJ81, Q6Y1H2, Q9P035, Q5VWC8; 3-hydroxyacyl-CoA dehydratases) and TECR (Q9NZ01, NADPH-dependent trans-2,3-enoyl-CoA reductase) catalyse the second, third and fourth reactions of the endoplasmic reticulum elongation cycle. ACOX1 (Q15067), peroxisomal acyl-CoA oxidase 1, FAD: initial and rate-limiting step of peroxisomal beta-oxidation, donating electrons directly to O2 to form H2O2; acts on tetracosahexaenoyl-CoA; possibly regulates systemic DHA through peroxisomal beta-oxidation of 24:6n-3 to DHA. HSD17B4 (P51659), peroxisomal multifunctional enzyme type 2: hydration of 2-enoyl-CoA and NAD+-dependent dehydrogenation of (3R)-3-hydroxyacyl-CoA, including the C24 hexaenoyl intermediates. ACAA1 (P09110), peroxisomal 3-ketoacyl-CoA thiolase: 3-oxo-tetracosahexaenoyl-CoA + CoA = docosahexaenoyl-CoA + acetyl-CoA. ACSL1 (P33121): a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-CoA + AMP + diphosphate. PTGS1 (P23219), prostaglandin G/H synthase 1, haem b, endoplasmic reticulum membrane: dual cyclooxygenase and peroxidase; the cyclooxygenase oxygenates arachidonate (20:4n-6) with 2 O2 to prostaglandin G2 and the peroxidase reduces it to prostaglandin H2, the precursor of all 2-series prostaglandins and thromboxanes. PTGS1 and PTGS2 (P35354) are the targets of NSAIDs including aspirin and ibuprofen; aspirin inactivates the enzyme irreversibly by serine acetylation (Ser-529 in PTGS1).
Independent research
Wene JD, Connor WE, DenBesten L. The development of essential fatty acid deficiency in healthy men fed fat-free diets intravenously and orally Journal of Clinical Investigation, 1975.
doi:10.1172/JCI108061 PubMed 806609
Funding and finding
Participants
9
Follow-up
28 days of fat-free feeding in Study I; 10 days of fat-free feeding, a 24-h fast, 3 days of intermittent feeding and 2 weeks of repletion in Study II
Funding
This paper was supported by research grants from the U. S. Public Health Service, National Heart and Lung Institute (HE-14,230), and from the General Clinical Research Centers Program (M01-FR-59) of the Division of Research Resources, National Institutes of Health.
Finding
In Study I, eight men received a eucaloric, fat-free diet of 80% glucose and 20% casein amino acid hydrolysate by constant 24-h infusion, 14 days intravenously and 14 days nasogastrically, in either order. In the four men fed intravenously first, linoleic acid fell from 48.8% to 9.8% of fatty acids in plasma cholesterol esters, from 21.2% to 3.2% in phospholipids, from 9.6% to 2.0% in free fatty acids and from 14.1% to 2.6% in triglycerides (P < 0.005); 5,8,11-eicosatrienoic acid, absent at baseline, reached 0.6%, 2.5%, 0.2% and 2.3%. Deficiency developed similarly with nasogastric feeding; dermatitis was not detected. In Study II, linoleic acid had fallen by day 3 of continuous feeding and rose during a 24-h fast; repletion with 2.6% of energy as linoleic acid corrected the deficiency by day 13. The authors state that, when linoleic acid is not present in adequate amounts, the same enzyme system elongates and desaturates oleic acid to 5,8,11-eicosatrienoic acid, a reaction competitively inhibited by linoleic acid.

Updated 2026-10-21