SiRNA-based inactivation of Angptl3 alleviates high-fat diet-induced MAFLD and atherosclerosis in LDLR-deficient hamsters

Q: What are the key findings of this study?

Angptl3-siRNA treatment reduced plasma triglycerides by 44.27% and total cholesterol by 31.37%, markedly decreased hepatic lipid accumulation, and attenuated atherosclerotic plaque formation in LDLR-/- hamsters fed a high-fat diet for 16 weeks.

Q: What is the clinical evidence from this study?

Population: Male 4-month-old LDLR-deficient (LDLR-/-) hamsters with high-fat diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis (n=12). Intervention: Angptl3 small interfering RNA (siRNA) delivered via recombinant adeno-associated virus serotype 9 (AAV9) vs. Empty AAV9 vector (AAV9-null). Primary outcome: Atherosclerotic plaque formation and hepatic lipid accumulation assessed by pathological analysis, Oil Red O and Sirius Red staining, and plasma lipid levels (p=<0.05).

Q: What question did this study set out to answer?

To investigate whether siRNA-mediated inactivation of Angptl3 alleviates hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in male LDLR-deficient hamsters fed a high-fat diet.

Xi Zhang; Yufei Han; Liwen Zheng; Xiaokui He; YunGang Pu; Lili Wei; Yuhui Wang; Xunde Xian

doi:10.1186/s12944-026-02916-3

March 5, 2026Lipids in Health and DiseaseOpen Access

SiRNA-based inactivation of Angptl3 alleviates high-fat diet-induced MAFLD and atherosclerosis in LDLR-deficient hamsters

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Key result

Angptl3-siRNA reduces triglycerides ~44% and attenuates atherosclerotic plaque and hepatic lipids in LDLR-/- hamsters.

P<0.05
n=12

Figures

Why the study?

Whether inhibition of Angptl3 can alleviate hepatic lipid accumulation and atherosclerosis remained unclear.

Does siRNA-based inactivation of Angptl3 reduce hepatic lipid accumulation and atherosclerosis in LDLR-deficient hamsters on a high-fat diet?

Key Points

To investigate whether siRNA-mediated inactivation of Angptl3 alleviates hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in male LDLR-deficient hamsters fed a high-fat diet.
Male 4-month-old LDLR−/− hamsters received jugular vein injections of recombinant AAV9 encoding Angptl3-siRNA or empty vector (AAV9-null).
All hamsters were fed a high-fat diet for 16 weeks to induce hyperlipidemia, MAFLD, and atherosclerosis.
Plasma lipid profiles, lipoprotein clearance, liver histology (Oil Red O, Sirius Red, Bodipy, CD68), and hepatic gene expression via RT-PCR were evaluated.
Angptl3-siRNA reduced liver Angptl3 expression by 74.57%, leading to a 44.27% decrease in plasma triglycerides and a 31.37% decrease in total cholesterol at 16 weeks compared with controls.
Plasma HDL-C decreased by 66.85% (121 mg/dL vs. 365 mg/dL) and glucose fell by 41.79% (241 mg/dL vs. 414 mg/dL), alongside reductions in VLDL/LDL fractions and accelerated clearance of triglyceride-rich lipoproteins.
Angptl3 silencing significantly reduced hepatic lipid accumulation, liver-to-body-weight ratio (0.043 vs. 0.054 mg/g), plasma ALT and AST, and atherosclerotic plaque formation in the aorta and aortic root.

Structured PICO

Does siRNA-based inactivation of Angptl3 reduce hepatic lipid accumulation and atherosclerosis in LDLR-deficient hamsters on a high-fat diet?

P

Population

12 male 4-month-old LDLR-/- hamsters fed a high-fat diet (0.2% cholesterol and 15% fat) for 16 weeks to induce atherosclerosis.

I

Intervention

Recombinant adeno-associated virus serotype 9 (AAV9) encoding Angptl3-siRNA injected via the jugular vein at a dose of 1x10^13 vg/kg.

C

Comparator

Empty AAV (AAV9-null) injected via the jugular vein.

O

Outcome

Hepatic lipid accumulation (MAFLD) and atherosclerotic plaque formation in the heart and aorta at 16 weeks.surrogate

Main Result

p-value: p=<0.05

SiRNA-based inactivation of Angptl3 effectively reduces hyperlipidemia, hepatic lipid accumulation, and atherosclerosis in an LDLR-deficient hamster model, suggesting a potential therapeutic target for cardiovascular and liver disease.

Limitations

Study conducted in an animal model (LDLR-/- hamsters), limiting direct applicability to humans.
Small sample size (n=12) with no reported randomization or blinding.
Primary endpoints are based on histological and biochemical surrogate measures, not clinical cardiovascular events.
No long-term safety or off-target effects of Angptl3-siRNA assessed.

Implication

Should not yet change clinical practice; extends ANGPTL3 as therapeutic target in preclinical atherosclerosis models.

Abstract

Angiopoietin-like protein 3 (Angptl3), a factor secreted by the liver, inhibits lipoprotein lipase and other lipases by forming a complex with Angptl4 and 8. However, whether inhibition of Angptl3 can alleviate hepatic lipid accumulation and atherosclerosis remains unclear. Therefore, this study explored the effect of small interfering RNA (siRNA)-based inactivation of Angptl3 on metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis in male LDLR-deficient hamsters. Recombinant adeno-associated virus serotype 9 (AAV9) encoding Angptl3-siRNA or empty AAV (AAV9-null) were injected into male 4-month-old LDLR−/− hamsters via the jugular vein. Subsequently, all hamsters were administered with a 16-week high-fat diet (HFD) feeding to induce atherosclerosis. RT-PCR and pathological analysis were used to investigate the mechanism of hepatic lipid accumulation and detect atherosclerotic plaque formation in the heart and aorta. On HFD, Angptl3-siRNA-treated hamsters displayed significantly decreased plasma triglyceride (TG), total cholesterol, high-density lipoprotein-cholesterol, and glucose levels, compared with the AAV9-null hamsters. FPLC analysis further revealed a marked reduction of TG and cholesterol contents in VLDL/LDL fractions. Plasma apolipoprotein analysis showed relatively lower ApoB/ApoE levels and higher ApoA1 levels. Moreover, Angptl3-siRNA markedly accelerated the clearance of triglyceride-rich lipoproteins in LDLR−/− hamsters. Consistently, results from hepatic lipid extraction, Oil Red O and Sirius Red staining demonstrated that Angptl3-siRNA reduced hepatic lipid accumulation and ameliorated HFD-induced MAFLD. RT-PCR revealed a dramatic decrease in the expression of Acc1, Fasn, Srebp1c, Cd36, Fatp1, Tgfβ, Cd68, Tnfa, and Col1a1 as well as a marked increase in Abcg5, Abcg8, Ppara, and Cpt1 expression, which participated in fatty acid synthesis and oxidation, cholesterol synthesis and efflux, inflammation and fibrosis. Pathological analysis indicated that Angptl3-siRNA attenuated the formation of atherosclerotic plaques in the aortic root and aorta when compared with the control group. These findings demonstrated that siRNA-based inactivation of Angptl3 alleviated MAFLD and atherosclerosis induced by HFD in LDLR−/− hamsters, which further confirmed that inhibition of Angptl3 may provide a novel therapeutic approach for atherosclerosis by reducing hyperlipidemia and hepatic lipid accumulation.

Discussion

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Cite This Study

Zhang et al. (2026) studied Male 4-month-old LDLR-deficient (LDLR-/-) hamsters with high-fat diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis (n=12). Angptl3 small interfering RNA (siRNA) delivered via recombinant adeno-associated virus serotype 9 (AAV9) vs. Empty AAV9 vector (AAV9-null) was evaluated on Atherosclerotic plaque formation and hepatic lipid accumulation assessed by pathological analysis, Oil Red O and Sirius Red staining, and plasma lipid levels (p=<0.05). Angptl3-siRNA treatment reduced plasma triglycerides by 44.27% and total cholesterol by 31.37%, markedly decreased hepatic lipid accumulation, and attenuated atherosclerotic plaque formation in LDLR-/- hamsters fed a high-fat diet for 16 weeks.

synapsesocial.com/papers/69abc2355af8044f7a4eb8e6 https://doi.org/10.1186/s12944-026-02916-3

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SiRNA-based inactivation of Angptl3 alleviates high-fat diet-induced MAFLD and atherosclerosis in LDLR-deficient hamsters

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

SiRNA-based inactivation of Angptl3 alleviates high-fat diet-induced MAFLD and atherosclerosis in LDLR-deficient hamsters

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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