(P24-126-23) Methionine Prevents the Progression of NASH to Cirrhosis in High Cholesterol Fed Sprague Dawley Rats Administered Sitagliptin

Objectives: Inflammatory diseases like atherosclerosis, stroke and non-alcoholic steatohepatitis (NASH) that progresses to cirrhosis are associated with hypercholesterolemia and hyperhomocysteinemia. Both, cholesterol (Cho) and Methionine (Met), precursor of homocysteine (Hcy) are rich in foods of animal origin like meat, dairy and poultry extensively consumed in the US. Independently Cho and Met/Hcy have been studied in the vascular tissue, but the combined effect of Cho and Met are not well studied especially in the liver. Therefore, we aimed to study the hepatic effects of the combination diet (Met+Cho). Also, sitagliptin a DPP-4 inhibitor and an anti-diabetic (type-2) drug that has anti-inflammatory and anti-oxidative properties (independent of glucose lowering) was studied to see if it is beneficial.

Methods: Adult male SD rats (4 groups) were fed ad libitum a control, or enriched with 1.5% Met, or 2.0% Cho, or their combination (1.5% Met+ 2.0% Cho) for 35 days. In the next experiment, from day 10-35, rats were orally gavaged with sitagliptin (100 mg/kg/d). Standard methods were used for processing the tissues and analysis.

Results: Hepatic inflammation and oxidative stress were anticipated to be seen in rats fed high Met, high Cho and an additive effect in Met+Cho diet. Only rats on high Cho had increases in hepatic inflammation and oxidative stress. The rats on high Met did not differ from Con rats, but lowered the high Cho mediated effects implying a beneficial response of Met. Serendipitously sitagliptin instead of lowering inflammation and oxidative stress, exacerbated them in the livers of high Cho rats. Interestingly, when Met was added to Cho (Met+Cho), even the exacerbations of pathology in high Cho animals due to sitagliptin were significantly alleviated, corroborating the beneficial effects of Met even further^1-3. Cho inducing the initiation and progression of NASH to cirrhosis (heme oxygenase 1, Lysyl oxidase 1) was hastened by sitagliptin while Met remarkably prevented this.

Conclusions: Met in combination with Cho, significantly prevents the hepatic inflammation and disease progression and thus may have a translational relevance.

1. Kumar A et al. (2020) Nutrition & Metabolism. 17:2.

2 & 3. Pathak R et al. (2019, 2022) Inflamm Res. 68 (7):581-595; 71:711-722

Funding Sources: Institutional Development Award (NIGMS/NIH) / Louisiana Biomedical Research Network