The researchers showed that albino mice on the C57BL / 6 line develop an inflammatory condition of hepatic non-alcoholic steatohepatitis (NASH) very quickly when on a high-cholesterol diet. Albino mice carry a mutation in the tyrosinase gene that leads to insufficient melanin synthesis. NASH is a serious disease in humans, and recognition of the involvement of tyrosinase in the development of NASH will lead to future research into this condition.
Non-alcoholic fatty liver disease (NAFLD) is an accumulation of fat in the liver that is not associated with alcohol abuse or other liver diseases. It is often associated with obesity and diabetes and is considered a manifestation of metabolic syndrome. With the onset of inflammation, it turns into non-alcoholic steatohepatitis (NASH), although it is currently unclear how it occurs. NASH can lead to serious complications such as liver failure, cirrhosis, and liver cancer. A team led by Tsukuba University has now found that albino mice with mutations at the tyrosinase gene site are more susceptible to NASH than mice carrying the unmutated gene. It is known that the prevalence and severity of NAFLD vary between different human ethnic groups, with the highest prevalence in the Hispanic population.
The tyrosinase gene encodes an enzyme involved in the production of melanin, which affects skin tone. In a preliminary computational analysis, the team observed that different point mutations in the tyrosinase gene also differed in frequency between different ethnic groups, with two major high-frequency variants being observed in the Hispanic population. Therefore, the researchers hypothesized that tyrosinase gene variants could potentially affect the sensitivity and hardness of NAFLD and NASH.
The team studied a specific mouse line known as "C57BL / 6" or B6 to test this hypothesis. Albino B6 mice had a mutation, known as a point mutation, in the tyrosinase gene. This affects the function of the enzyme tyrosinase, so albino mice cannot properly produce melanin, lose pigmentation and turn white instead.
Dietary cholesterol contributed to the development of hepatitis, so a group of albino and black B6 mice followed a high cholesterol diet for 10 weeks. They found that black B6 mice showed no symptoms during the diet, while about 50% of albino B6 mice showed a severe phenotype that promotes liver damage.
The team further showed that B6 albino mice showed high tyrosinase expression in the small intestine. "This can affect the sensitivity of NASH mice by affecting the increase in cholesterol in the small intestine," says lead author, Assistant Professor Michito Hamada, "pointing to a possible mechanism for this rate increase."
"Because the point mutation in the tyrosinase gene is the only genetic difference between albino B6 and black B6 mice," explained Professor Hamada, "our work will facilitate the identification of genetic predisposition factors for NASH development and a growing understanding of NASH. pathophysiology. ".
Article source: Kaushalya Kulathunga, Arata Wakimoto, Yukiko Hiraishi, Manoj Kumar Yadav, Kyle Gentleman, Eiji Warabi, Tomoki Sakasai, Yoshihiro Miwa, Seiya Mizuno, Satoru Takahashi, Michito Hamada. Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility.