Medical Biochemistry - Lipids

Lipids are a diverse group of hydrophobic or amphipathic biomolecules that serve as structural components of cell membranes, energy stores and signalling mediators. Major classes include fatty acids, glycerolipids (triacylglycerols), glycerophospholipids and sterols. Fatty acids are synthesised de novo from acetyl–coenzyme A and can be esterified to form storage triacylglycerols in lipid droplets or incorporated into membrane phospholipids. Cholesterol, produced via the mevalonate pathway, modulates membrane fluidity, serves as a precursor for steroid hormones and bile acids, and is esterified by acyl‐CoA:cholesterol acyltransferases for intracellular storage. Lipid transport involves lipoprotein assembly (chylomicrons, VLDL, LDL, HDL), receptor‐mediated uptake and reverse cholesterol transport. Dysregulation of lipid metabolism underpins a range of diseases—from atherosclerosis and fatty-liver disease to inherited enzyme defects in cholesterol biosynthesis. Recent advances in lipidomics, structural biology and enzymology have elucidated key regulators of lipid flux, interconnections with inflammatory and metabolic pathways, and novel therapeutic targets to restore lipid homeostasis.

Research from Nature Portfolio

Studies have identified adipose triglyceride lipase (ATGL) as a genuine biosynthetic enzyme for branched fatty acid esters of hydroxy fatty acids (FAHFAs). In vitro and in vivo experiments demonstrated that ATGL catalyses a transacylation reaction transferring fatty acids from triglycerides onto hydroxy fatty acids, with genetic or pharmacological inhibition of ATGL reducing FAHFA levels by over 80% in adipose tissue. This finding redefines ATGL’s role from mere lipolysis to also governing pools of anti‐inflammatory signalling lipids.

Inflammation‐induced insulin resistance has been mechanistically linked to an IRF3–AIG1 axis in adipocytes. Activation of interferon regulatory factor 3 (IRF3) upregulates the hydrolase AIG1, promoting FAHFA hydrolysis, diminishing protective FAHFA pools and impairing glucose homeostasis. Knockout of IRF3 or pharmacological blockade of AIG1 restores FAHFA levels and insulin sensitivity on high-fat feeding, highlighting inflammation‐driven remodelling of lipid-signalling metabolites.

Long‐term statin treatment in diabetic mouse models was shown to exacerbate kidney injury by perturbing lipid metabolism. Chronic inhibition of HMG-CoA reductase unexpectedly activated PI3K–AKT–mTOR signalling, driving upregulated de novo lipogenesis and increased lipid uptake while suppressing fatty-acid oxidation. The consequent ectopic fat deposition in renal tissues intensified inflammation and fibrosis, underscoring the complex balance between systemic cholesterol lowering and tissue‐specific lipid homeostasis.

Medical Biochemistry - Lipids publication trend

The graph below shows the total number of articles in medical biochemistry - lipids across all publications each year (not limited to Nature Index journals).

Technical terms

De novo lipogenesis (DNL): Metabolic pathway synthesising fatty acids from acetyl–CoA, often upregulated in metabolic disease.

Transacylation: Enzymatic transfer of an acyl group from one lipid (e.g. triglyceride) to another molecule (e.g. hydroxy fatty acid) to generate signalling lipids.

FAHFAs: Branched fatty acid esters of hydroxy fatty acids—a class of anti-inflammatory signalling lipids synthesised and hydrolysed by ATGL and hydrolases such as AIG1.

AIG1: Androgen-induced gene 1, a threonine hydrolase that degrades FAHFAs and links inflammatory transcription to lipid-signalling pools in adipocytes.

MAGL: Monoacylglycerol lipase, an enzyme that hydrolyses monoacylglycerols (including 2-arachidonoylglycerol), protecting against ectopic lipid accumulation and fibrosis in renal tubules.

Ectopic fat deposition: Accumulation of lipid droplets within non-adipose tissues, leading to cellular dysfunction and inflammation.

References

1. MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity. Theranostics (2024).
2. ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules. Journal of Clinical Investigation (2023).
3. Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice. Nature Communications (2023).
4. ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids. Nature (2022).
5. Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels. Nature Communications (2024).
6. An Overview of Lipid Metabolism.