Related Experiment Video
Updated: Jul 16, 2025
08:35
A Model of Experimental Steatosis In Vitro: Hepatocyte Cell Culture in Lipid Overload-Conditioned Medium
Published on: May 18, 2021
6.4K
ANGPTL3 Deficiency and Risk of Hepatic Steatosis
Laura D'Erasmo1, Michele Di Martino2, Thomas Neufeld3
1Departments of Translational and Precision Medicine (L.D'E., A.D.C., I.M., S.B., M.M., G.P., A.M., M.A.), Sapienza University of Rome, Italy.
Circulation
|September 15, 2023
Summary
ANGPTL3 deficiency, whether genetic or induced, does not increase hepatic fat. Inhibiting ANGPTL3 (angiopoietin-like 3) production is unlikely to cause hepatic steatosis, despite prior observations.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Metabolic Disorders
Background:
- Angiopoietin-like 3 (ANGPTL3) is a key regulator of plasma lipid levels.
- Inhibition of ANGPTL3 lowers triglycerides and LDL cholesterol.
- A recent trial noted increased hepatic fat with vupanorsen, an ANGPTL3 inhibitor, raising questions about on-target effects.
Purpose of the Study:
- To investigate the association between ANGPTL3 deficiency and hepatic fat accumulation.
- To determine if ANGPTL3 inhibition causally impacts hepatic fat content.
- To clarify the safety profile of ANGPTL3-targeted therapies regarding hepatic steatosis.
Main Methods:
- Recruited participants with ANGPTL3 loss-of-function (LoF) mutations and wild-type controls.
- Utilized magnetic resonance spectroscopy and proton density fat fraction to assess hepatic and extrahepatic fat.
- Performed Mendelian randomization analyses using UK Biobank data to establish causal relationships.
Main Results:
- ANGPTL3 deficiency was associated with significantly lower LDL cholesterol and triglycerides.
- No significant difference in hepatic fat fraction or steatosis severity was observed between ANGPTL3-deficient and wild-type individuals.
- Mendelian randomization confirmed ANGPTL3's causal role in regulating LDL cholesterol and triglycerides, but not hepatic fat.
Conclusions:
- Genetic ANGPTL3 deficiency is not linked to hepatic steatosis.
- Therapeutic inhibition of ANGPTL3 production is unlikely to increase the risk of hepatic steatosis.
- Findings suggest that the hepatic fat increase observed with vupanorsen may not be a direct consequence of ANGPTL3 inhibition.
