Premium
Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH
Author(s) -
Amrutkar Manoj,
Cansby Emmelie,
NuñezDurán Esther,
Pirazzi Carlo,
Ståhlman Marcus,
Stenfeldt Elin,
Smith Ulf,
Borén Jan,
Mahlapuu Margit
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-264937
Subject(s) - nonalcoholic fatty liver disease , steatosis , lipid droplet , medicine , endocrinology , insulin resistance , fatty liver , steatohepatitis , adipose tissue , adipose triglyceride lipase , biology , protein kinase a , chemistry , kinase , insulin , biochemistry , lipolysis , disease
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease, and 10% to 20% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH). The molecular pathways controlling progression to NAFLD/NASH remain poorly understood. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of whole‐body insulin and glucose homeostasis. This study investigates the role of STK25 in liver lipid accumulation and NASH. Stk25 transgenic mice challenged with a high‐fat diet displayed a dramatic increase in liver steatosis and hepatic insulin resistance compared to wild‐type siblings. Focal fibrosis, hepatocellular damage, and inflammation were readily seen in transgenic but not wild‐type livers. Transgenic livers displayed reduced β‐oxidation and triacylglycerol secretion, while lipid uptake and synthesis remained unchanged. STK25 was associated with lipid droplets, colocalizing with the main hepatic lipid droplet‐coating protein adipose differentiation‐related protein, the level of which was increased 3.8 ± 0.7‐fold in transgenic livers ( P < 0.01), while a key hepatic lipase, adipose triacylglycerol lipase, was translocated from the lipid droplets surface to the cytoplasm, providing the likely mechanism underlying the effect of STK25. In summary, STK25 is a lipid droplet‐associated protein that promotes NAFLD through control of lipid release from the droplets for β‐oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.—Amrutkar, M., Cansby, E., Nuñez‐Durán, E., Pirazzi, C., Ståhlman, M., Stenfeldt, E., Smith, U., Borén, J., Mahlapuu, M. Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH. FASEB J. 29, 1564‐1576 (2015). www.fasebj.org