Michael Karin, Ph.D.
University of California, San Diego
NIEHS grantees discovered that a protein-cleaving enzyme known as caspase-2 is a major driver of nonalcoholic steatohepatitis (NASH), which is the most aggressive form of nonalcoholic fatty liver disease (NAFLD). They reported that caspase-2 controls the buildup of cholesterol and triglycerides in liver tissue by activating sterol regulatory element binding proteins, the master regulators of fatty tissue formation in the liver.
Researchers used mice susceptible to liver-specific endoplasmic reticulum stress, a factor that accelerates the progression of benign NAFLD, and fed them a high-fat diet to elicit NASH-like disease. Using this model, the scientists measured changes to enzymes during NASH progression and found that the onset of NASH correlated with increased expression of caspase-2.
When they knocked out the caspase-2 gene in the mice, the team observed reductions in all aspects of NASH, including lipid droplet accumulation as well as liver damage, inflammation, and scarring. The researchers also observed decreased NASH progression when they treated the mice with a specific caspase-2 inhibitor.
Examination of human liver specimens from patients with benign NAFLD or aggressive NASH, confirmed that caspase-2 expression was also elevated in humans with NASH. According to the authors, an inhibitor of this enzyme may potentially provide an effective way to stop the progression that leads to NASH, and possibly even reverse early symptoms.
Citation: Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, Kaufman RJ, Saltiel AR, Karin M. 2018. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 175(1):133-145.e15.