2020-P: Comparable Disease Progression in GAN and AMLN Diet-Induced Obese Mouse Models of Biopsy-Confirmed Nonalcoholic Steatohepatitis

Amylin Liver NASH (AMLN) diet-induced obese C57Bl/6J (DIO-NASH) and ob/ob (ob/ob-NASH) mouse models display clinical translatability with respect to metabolic and histopathological changes associated with nonalcoholic steatohepatitis (NASH). A recent FDA ban on trans-fats in foods has necessitated the development of a new NASH diet capable of promoting comparable disease, as AMLN diet contains trans-fat-containing Primex shortening. Here, we assessed the disease phenotype in C57Bl/6J and ob/ob mice fed a high-fat diet with a nutrient composition and caloric content comparable to the AMLN diet. Male ob/ob mice were fed AMLN diet (40% total fat kcal of which 18.5% were trans-fat kcal; 20% fructose; 2% cholesterol) for 16 weeks or a modified AMLN diet with Primex substituted by palm oil, termed Gubra Amylin NASH (GAN) diet, for up to 30 weeks. C57 mice were fed GAN diet for 28 weeks. In ob/ob-NASH mice, GAN diet was more obesogenic and adipogenic than the AMLN diet. GAN, but not AMLN, diet also impaired glucose tolerance in ob/ob-NASH mice versus chow-fed C57Bl/6J mice. Both diets promoted similar levels of steatosis, lobular inflammation and hepatocyte ballooning as well as similar fibrotic liver lesions and collagen-1a1 fractional area. Mild (stage F1) and moderate (stage F2) grade fibrosis was induced in DIO-NASH and ob/ob-NASH mice, respectively, when fed either diet for 16 weeks. When fed GAN diet for ≥24 weeks, a significant proportion of ob/ob-NASH mice developed advanced fibrosis (stage F3). The two diets also promoted overlapping liver transcriptome changes. In conclusion, AMLN diet modification by substitution of Primex with palm oil results in a preserved NASH phenotype in C57 and ob/ob mice. Accordingly, the GAN diet induced clear metabolic and histopathological hallmarks of biopsy-confirmed NASH in both DIO-NASH and ob/ob-NASH mice, highlighting the suitability of these models for the characterization of novel drug therapies for NASH. Disclosure B.B. Boland: Employee; Self; Gubra, MedImmune. H.H. Hansen: None. M. Boland: Employee; Self; Gubra, MedImmune. D. Oró: None. K.S. Tølbøl: None. S. Veidal: None. M. Feigh: None. J. Jelsing: Stock/Shareholder; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Trevaskis: Employee; Self; Gilead Sciences, Inc., MedImmune. Stock/Shareholder; Self; AstraZeneca.