A newly discovered genetic link to non-alcohol

image: Photo by WAKIMOTO Arata
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Credit: University of Tsukuba

Tsukuba, Japan – Non-alcoholic fatty liver disease (NAFLD) is the buildup of fat in the liver unrelated to alcohol abuse or other liver diseases. It is often associated with obesity and diabetes and is considered a manifestation of the metabolic syndrome. It progresses to non-alcoholic steatohepatitis (NASH) with the onset of inflammation, although it is not yet clear how this occurs. NASH can lead to serious complications such as liver failure, cirrhosis and liver cancer. Now, a team led by the University of Tsukuba has found that albino mice with a point mutation in the tyrosinase gene are more susceptible to NASH than mice with the unmutated gene.

The prevalence and severity of NAFLD are known to vary between different human ethnicities, with the highest prevalence in Hispanic populations. The tyrosinase gene codes for an enzyme involved in the production of melanin, affecting skin tone. The team observed in preliminary computational analyzes that different point mutations in the tyrosinase gene also vary in frequency between different ethnic groups, with the two main variants being seen at high frequencies in Hispanic populations. The researchers therefore hypothesized that variants of the tyrosinase gene could possibly affect the susceptibility and severity of NAFLD and NASH.

The team studied a particular line of mice known as “C57BL/6”, or B6, to test this hypothesis. B6 albino mice have a single change, known as a point mutation, in the tyrosinase gene. This affects the function of the enzyme tyrosinase so that albino mice cannot produce melanin properly, losing their pigmentation and turning white instead of black.

Dietary cholesterol contributes to the development of liver inflammation, so the team fed B6 albino and black mice a high-cholesterol diet for 10 weeks. They found that the black B6 mice showed no symptoms throughout the diet, while around 50% of the albino B6 mice showed a severe phenotype, developing liver damage after just one day that progressed to NASH after 2 weeks. .

The team further showed that B6 albino mice had elevated expression of tyrosinase in the small intestine. “This could affect the susceptibility of mice to NASH by affecting cholesterol absorption in the small intestine,” says lead author Assistant Professor Michito Hamada, “indicating a potential mechanism for this increased susceptibility.”

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

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The article, “Albino mice with the point mutation at the tyrosinase locus show high-cholesterol diet-induced NASH susceptibility,” was published in Scientific reports at DOI: 10.1038/s41598-021-00501-5

This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (26221004, 25860205, 23118504, 16K18398, 19K07499, 19H00966); Uehara Memorial Foundation; Takeda Science Foundation; the Takamatsunomiya Cancer Foundation (15-24724; M. Hamada); and the World Premier International Research Center Initiative (WPI), MEXT, Japan.


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