How does de novo lipogenesis work?
De novo lipogenesis is the cell's route from acetyl-CoA to fatty acids, and it is dysregulated in fatty liver disease and in arrhythmogenic cardiomyopathy. This page covers the pathway, its rate-limiting enzyme FASN, and
De novo lipogenesis (DNL) is the metabolic pathway by which cells build fatty acids from non-fat precursors, principally acetyl-CoA derived from carbohydrate and, to a lesser extent, amino acid catabolism. It is distinct from dietary fat uptake and from lipolysis of stored triglyceride: DNL is synthesis from scratch. The pathway is cytosolic in mammals and proceeds through acetyl-CoA carboxylase (ACC), which converts acetyl-CoA to malonyl-CoA, then through fatty acid synthase (FASN), the multi-domain enzyme that carries out the iterative condensation, reduction, dehydration and reduction steps that extend the acyl chain. FASN is generally described as the rate-limiting enzyme of the pathway. The evidence block for this page does not supply a sequence, formula or molecular weight for FASN, so none is given here.
The work summarised below centres on the FASN arm of the lipogenic pathway and on its relationship to hepatic lipid handling and to cardiomyocyte lipid metabolism.
Research Studies
FASN and ceramide accumulation in arrhythmogenic cardiomyopathy
In arrhythmogenic cardiomyopathy (ACM), a heritable disease caused by desmosomal gene mutations and characterised by progressive myocardial loss and fibrofatty replacement, FASN was reported to be upregulated in cardiomyocytes of ACM patients and of a corresponding animal model. The same work linked FASN-mediated de novo lipogenesis to ceramide accumulation and to myocardial damage [2]. This is a disease-model finding; it does not establish that the same mechanism operates in healthy human myocardium.
Hepatic steatosis and the definition of NAFLD
Non-alcoholic fatty liver disease (NAFLD) is defined as excessive lipid accumulation within hepatocytes in the absence of significant alcohol consumption or other causes of chronic liver disease. The minimum criterion for a histological diagnosis is greater than 5 percent of hepatocytes showing steatosis. NAFLD affects an estimated 25 to 30 percent of the global population and nearly one third of the population in North America [1]. DNL is one of the processes that can contribute lipid to the hepatocyte pool, alongside dietary fatty acid delivery and adipose-derived free fatty acid flux.
Insulin resistance and the clinical context of hepatic lipid accumulation
Patients with hepatic steatosis typically present with elevated liver enzymes and features of insulin resistance, including pre-diabetes, type 2 diabetes mellitus, arterial hypertension, dyslipidemia and visceral obesity [1]. These are clinical associations reported in the study population; they describe the context in which hepatic lipid accumulation is observed, not a causal role for any single enzyme.
Diet and hepatic transcriptomics in pre-diabetes
A registered study has examined how diet affects hepatic transcriptomics and lipidomics in pre-diabetes [1]. The design addresses the question of whether dietary manipulation shifts the transcriptional programme of the liver and the lipid species it contains. The evidence block does not report the outcome measures or results of that study, so no effect size or direction is stated here.
Comparing the two tissue contexts in the evidence
| Tissue / model | Lipogenic enzyme implicated | Lipid species or readout reported | Source |
|---|---|---|---|
| Human and animal cardiomyocytes in ACM | FASN | Ceramide accumulation, myocardial damage | [2] |
| Human liver in NAFLD | Not specified in the evidence | Hepatocyte lipid accumulation, steatosis on imaging | [1] |
What the pathway does at the enzyme level
ACC produces malonyl-CoA, the two-carbon donor used at each elongation cycle, and FASN consumes it. Because malonyl-CoA is both a substrate for FASN and an inhibitor of carnitine palmitoyltransferase 1, the entry step for fatty acid oxidation, the lipogenic and oxidative arms of lipid metabolism are reciprocally regulated at this node. The evidence block does not contain primary data on ACC or on CPT1, so this paragraph describes the pathway as generally understood rather than reporting a study result.
Where the evidence is animal-only or in vitro
The ACM findings on FASN upregulation and ceramide accumulation were reported in patient cardiomyocytes and in a corresponding model system [2]. The NAFLD prevalence and histological criteria figures are population-level and clinical [1]. No in vitro-only claim is made on this page, because the evidence block does not supply one.
Limits of the evidence base for this page
Two sources are cited. One is a registered study record that supplies background definitions and epidemiology but not results [1]; the other is a reference-only report whose findings are summarised here in our own words [2]. Neither source provides a quantitative measure of DNL flux, so no rate, fold-change or flux value is stated.
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Sources
- [1] Diet Impact on Hepatic Transcriptomics and Lipidomics in Pre-diabetes — ClinicalTrials.gov, public domain.
- [2] FASN-mediated de novo lipogenesis promotes ceramide accumulation and myocardial damage in arrhythmogenic cardiomyopathy — PubMed.