Moderately-High Fat Diet Exacerbates Some but Not All Phenotypes of a Murine LCHADD Model

Author

• Ayah Asal, Portland State UniversityFollow

First Advisor

Melanie Gillingham

Date of Award

Spring 6-2026

Document Type

Thesis

Degree Name

Bachelor of Science (B.S.) in Biology and University Honors

Department

Biology

Language

English

Subjects

Metabolism, Physiology, Fatty Acids, Genetics, Lipids, Triglycerides

Abstract

Background: Long-Chain 3-Hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a recessive disorder of fatty acid oxidation predominantly due to the pathogenic variant, c.1528G>C in the HADHA gene. Despite current treatments, patients with LCHADD develop acute episodes of hypoketotic hypoglycemia, recurrent rhabdomyolysis, cardiomyopathy, and hepatomegaly. Previously, the Gillingham Lab developed a murine LCHADD model by inserting the c.1528G>C variant in C57BL/6J with CRISPR/Cas9. LCHADD mice recapitulate the human phenotype when fed regular rodent chow (13.6% kcal fat) at one year of age. We fed LCHADD and WT mice a diet comprised of 21.6% kcal of fat to determine if a moderately high-fat diet would exacerbate the LCHADD phenotype.

Methods: After 10 months on a moderately high-fat diet, mice were weighed and lean and fat mass were measured using EchoMRI. Mice were run on a treadmill to exhaustion to test exercise capacity. Pre- and post-exercise blood glucose and ketones were measured to observe glucose and fat utilization. Triglyceride (TGY) concentration and Oil-Red-O staining was used in hearts and livers to measure lipid accumulation in tissues. Tissue long-chain fatty acid oxidation (FAO) flux was measured using a colorimetric assay. This study was compared to previously measured results on regular chow.

Results: LCHADD mice on the moderately high-fat chow gained less weight and had lower body fat than WT. LCHADD mice ran less distance with lower ketones. WT males were hyperglycemic after exercise. In liver, TGY concentrations, Oil-Red-O staining, and FAO flux were not different between genotypes on moderately high-fat chow even though we previously observed increased TGY and lower FAO flux in LCHADD mice on regular chow. However, Oil-Red-O staining in the heart showed increased lipid content and FAO flux was significantly lower in LCHADD hearts compared to WT on the moderately high-fat diet.

Conclusions: Higher body weight, blood glucose levels, liver triglycerides, and no difference in liver FAO flux results suggest that a moderately high-fat diet may be inducing metabolic syndrome in WT mice. In contrast, a moderately high-fat diet did not appear to increase body fat, raise blood glucose, or worsen LCHADD exercise capacity. While a moderately high-fat chow did not impact all the LCHADD phenotypes, it had negative effects on WT mice, which diminished differences between genotypes. Future experiments must consider the overall impact of moderately high-fat chow.

Persistent Identifier

https://archives.pdx.edu/ds/psu/44786

Recommended Citation

Asal, Ayah, "Moderately-High Fat Diet Exacerbates Some but Not All Phenotypes of a Murine LCHADD Model" (2026). University Honors Theses. Paper 1816.