Significance While the MAPK p38α is highly active in nonalcoholic fatty liver disease (NAFLD), whether its constitutive activity is a driver or mere consequence of pathology remains unclear. This was not answered due to the lack of methods for specific p38α activation in vivo. A transgenic mouse model allowing inducible expression of an intrinsically active p38α variant in a tissue-specific manner meets this challenge. Upon expression of the active p38α allele in the liver, mice develop lipidosis (fatty liver) within four weeks without gaining overweight. This study shows that fatty liver could occur in response to activation of a single protein and provides the first genetic model for revealing the etiology of fatty liver diseases from the point of their trigger.