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Genetic point mutation linked to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a metabolic condition that has a high global prevalence and is rapidly growing. Researchers discovered that albino mice with a mutant tyrosinase gene are more susceptible to the inflammatory liver disease, non-alcoholic steatohepatitis.

The buildup of fat in the liver, unrelated to alcohol misuse or other liver illnesses, is known as non-alcoholic fatty liver disease (NAFLD). NAFLD is frequently linked to obesity and diabetes, and it’s considered a symptom of metabolic syndrome. With the development of inflammation, it proceeds to non-alcoholic steatohepatitis (NASH), albeit how this happens is still unknown.

NASH can result in serious consequences such as liver failure, cirrhosis, and malignancy. However, researchers from the University of Tsukuba have discovered that albino mice with a point mutation in the tyrosinase gene are more prone to NASH than mice without the mutation.

NAFLD is known to vary in incidence and severity among different ethnicities, with Hispanic populations having the highest prevalence. The tyrosinase gene produces an enzyme that affects skin tone by regulating melanin synthesis. In preliminary computer analysis, the researchers discovered that the prevalence of various point mutations in the tyrosinase gene varies by ethnic group, with the two primary variations being found at high frequencies in Hispanic populations. As a result, the researchers postulated that tyrosinase gene variations might influence NAFLD and NASH susceptibility and severity.

A liver tissue sample demonstrating non-alcoholic fatty liver disease. (Credit: Flickr/NIH Image Gallery)

To test this theory, the researchers looked at a mouse strain known as “C57BL/6,” or B6. The tyrosinase gene in albino B6 mice has a single alteration, known as a point mutation. This interferes with the activity of the tyrosinase enzyme, causing albino mice to lose their pigmentation and become white instead of black.

Because dietary cholesterol has a role in the development of liver inflammation, the researchers provided high-cholesterol diets to albino and black B6 mice for 10 weeks. They discovered that black B6 mice displayed no signs throughout the diet, but albino B6 mice had a severe phenotype, establishing liver damage after just one day and progressing to NASH after two weeks.

The researchers also discovered that albino B6 mice had a high level of tyrosinase expression in the small intestine. “This could affect the susceptibility of the mice to NASH by affecting the uptake of cholesterol in the small intestine,” says senior author Assistant Professor Michito Hamada, “pointing to a potential mechanism for this increased susceptibility.”

“As the point mutation in the tyrosinase gene is the only genetic difference between B6 albino and B6 black mice,” explains Assistant Professor Hamada, “our work will facilitate the identification of genetic susceptibility factors for the development of NASH and expand the understanding of the pathophysiology of NASH.”

The study was published in Scientific Reports, on November 8th, 2021.

Abstract. Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyrc-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.

Kulathunga, K., Wakimoto, A., Hiraishi, Y. et al. Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility. Sci Rep 11, 21827 (2021).

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