Resmetirom protects against diet-induced MASLD and reduces
atherosclerosis development in obese LDLR-/-.Leiden mice
Eveline Gart1, Wim van Duyvenvoorde1, Nikki van Trigt1, Robert Kleeman1, Geurt Stokman1, Martine Morrison1. 1 TNO Metabolic Health Research, The Netherlands;

4. Resmetirom reduced MASLD/MASH development
Chow

Resmetirom (Rezdiffra) is a potent lipid-lowering drug (thyroidhormone receptor-β agonist) and the first approved drug for
MASLD. Clinical trials have revealed its remarkable efficacy
in reducing plasma LDL cholesterol levels, suggesting its
potential impact on mitigating obesity-related cardiovasculardisease (CVD), the foremost contributor to mortality among
MASLD patients.

FFD -SOT

***
20***
020*

018 19 20 21 22 23 24 25 26 27 28

18202224*

*

2628*
*

5***

*

2628****

105***

202224Resmetirom reduced FFD-induced increased in plasma lipids
cholesterol and triglycerides in absence of an effect on bodyweight (BW).

FFD + Resmetirom

203210***15***1050***

15001000******

5000***

In line with the strong reduction in circulating lipids, resmetirom significantly
reduced the FFD-induced atherosclerosis lesion area compared to FFD + vehicle.

FFD + Resmetirom

FFD + vehicle

Resmetirom didn't impact
fibrosis area (SR) but did
decrease the number of animals***
progressing to stage 3 fibrosis.
It also significantly reduced
hepatic collagen compared toFFD, aligning with clinical
Phase 3 trial results.

1500

***

1000

***

500
100
500**

**

**

**

**
I

**
***

IIIIIIVVLesion severity analysis according to the American Heart Association (AHA)
scoring system reveals that resmetirom exhibits its most significant impact on
the lesion area of severe type V lesions.

5. Resmetirom improved atherogenic-lipid particles

7. Conclusion

The Ldlr-/-.Leiden mouse model mimics both human NASH and CVD through dietinduced conditions. While the LDLR alteration isn't the direct cause of NAFLD/NASH, it
effectively mirrors human lipid trafficking and vascular complications affecting vessels
HDL
VLDL
LDL
8
inside and outside the liver.

Resmetirom reduced MASLD/MASH and lowered plasma LDL-cholesterol,consistent with Phase 3 MAESTRO-NASH trial findings, highlighting therelevance of the Ldlr-/-.Leiden mouse model.
Additionally, it reduced atherosclerosis progression alongside its positiveeffects on the liver. Since obesity-related CVD remains a top cause of death in
MASH patients, our findings emphasize resmetirom's clinical potential as apromising therapy for MASH.

018

FFD -SOT

Resmetirom reduced FFDinduced macro- andmicrovesicular steatosis, as wellas liver inflammation, reachinglevels below those observed in
the FFD start-of-treatmentreference group.

Consistent with the plasma lipid lowering, the FFDinduced increase in atherogenic (V)LDL lipoproteinparticles were attenuated after 10 weeks ofresmetirom treatment, in line with the LDL-cholesterol
lowering by resmetirom in the clinical Phase 3 trial.

Lipoprotein profile
Cholesterol (mM)

25*

Triglycerides (mM)

Cholesterol (mM)

Body weight (g)

30*

10*

10*

0420015****

Hepatic collagen(mg/total liver weight)

3. Resmetirom improved metabolic risk
factors independent of BW effects

40***

2015

FFD SOT

Hepatic Fibrosis(stage 0-3)

Hepatic fibrosis(% of surface area)(n=8 chow mice;
n=15 FFD mice/grp)

35

40

Chow3060

200Ldlr-/-.Leiden mice were initially fed a fast-food diet (FFD) for
18 weeks to induce early MASLD and atherosclerosis. After
this period, one group was terminated as a start-of-treatment
reference (FFD SOT). The rest continued on FFD andreceived either vehicle or 3 mg/kg Resmetirom for an
additional 10 weeks before termination at t=28 weeks. Chowfed mice served as a healthy reference group.

40ChowLesion size per type2
per cross-section (*1000 um )40

60

Inflammation(# of aggregates/mm2)

60

Microvesicular steatosis(% of surface area)

Macrovesicular steatosis(% of surface area)

The study aimed to assess resmetirom's impact on CVD
progression (atherosclerosis) on top of its positive effects on
MASLD-associated liver fibrosis.

80

FFD + Resmetirom

FFD + Vehicle

FFD + Vehicle

2. Study aims and design45

6. Resmetirom attenuated atherosclerosis

Atherosclerotic lesion area
per cross-section (*1000 μm2)

1. Introduction

642004812162024

Contact information: eveline.gart@tno.nl