NEW INSIGHTS INTO THYROID HORMONE METABOLISM AND AMMONIA DETOXIFICATION IN MASLD USING N-ACETYLCYSTEINE (NAC) AND L-ORNITHINE L-ASPARTATE (LOLA)

Introduction and Objectives

Thyroid hormones (THs) are fundamental to liver physiology. TH dysfunction, particularly due to alterations in deiodinase enzymes such as D3, plays a critical role in the progression of MASLD. In MASLD, the Urea Cycle and Krebs Cycle shift their enzymes to alternative pathways for ammonia detoxification, disrupting normal energy metabolism.

Materials and Methods

Adult male Sprague Dawley rats were randomly assigned to a control group on a standard diet (2.93 kcal/g, n=10), an intervention group on a high-fat diet deficient in choline (MASLD, HDCF, 4.3 kcal/g, n=10), and two treatment groups, MASLD+NAC (n=12) and MASLD+LOLA (n=12), over a period of 16 weeks.

Results

In MASLD, there was an increase in the expression of D3, colocalized with M1 macrophages and TR beta protein levels, while MCT8 levels remained unchanged. Additionally, mitochondrial respiration decreased, and no effects were observed with treatments. Furthermore, Glutamate Dehydrogenase (GDH) activity diminished, whereas α-Ketoglutarate Dehydrogenase (α-KGDH) activity increased. It was also determined that Grp78 (decreased by 74%) and Grp75 (increased by 60%) are regulated by T3 and are endoplasmic reticulum (ER) chaperones meaning ER stress.

Conclusions

Our study corroborates the interaction between TH metabolism and compensatory mechanisms that counteract elevated ammonia levels, as well as the enzymes regulating this process in MASLD. Both NAC and LOLA demonstrated potential in correcting TH metabolism and enhancing ammonia detoxification in MASLD, which may help alleviate symptoms or slow the progression of the disease.

Conflict of interest: None