Caspase-2 Drives Progression of Fatty Liver Disease

The enzyme caspase-2 has been shown to be critically linked to the progression of nonalcoholic fatty liver disease (NAFLD) to the more serious and aggressive nonalcoholic steatohepatitis (NASH) form of the syndrome.

NASH is the most aggressive form of non-alcoholic fatty liver disease, which includes a spectrum of chronic liver diseases and has become a leading cause of liver transplants. NAFLD progresses to NASH in response to elevated endoplasmic reticulum (ER) stress. While the onset of simple steatosis requires elevated de novo synthesis of lipids, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol.

Investigators at the University of California San Diego (USA) reported in the September 13, 2018, online edition of the journal Cell that caspase-2, whose expression was found to be ER-stress inducible and elevated in human and mouse NASH, controlled the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP).

Caspase-2 co-localized with site 1 protease (S1P) and cleaved it to generate a soluble active fragment that initiated SCAP (SREBP cleavage-activating protein)-independent SREBP1/2 activation in the ER. Elimination of caspase-2 or its pharmacological inhibition prevented diet-induced steatosis and NASH progression in ER-stress-prone mice.

"In NASH-free individuals, the activities of SREBP1 and SREBP2 are kept under control, which is essential for preventing excessive lipid accumulation in the liver," said senior author Dr. Michael Karin, professor of pharmacology at the University of California, San Diego. "However, in NASH patients, something goes awry and the liver continues to turn out excess amounts of triglycerides and cholesterol. This correlates with elevated SREBP1 and SREBP2 activities and increased caspase-2 expression. Our results show that caspase-2 is a critical mediator of NASH pathogenesis, not only in mice but probably in humans as well. While explaining how NASH is initiated, our findings also offer a simple and effective way to treat or prevent this devastating disease."

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