Journal
FASEB JOURNAL
Volume 29, Issue 4, Pages 1564-1576Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-264937
Keywords
lipid droplets; lipid metabolism; liver inflammation; NAFLD; steatohepatitis
Categories
Funding
- Swedish Research Council
- European Foundation for the Study of Diabetes/Lilly Research Program
- European Foundation for the Study of Diabetes
- Novo Nordisk Partnership for Diabetes Research in Europe (Dusseldorf, Germany)
- Novo Nordisk Foundation (Hellerup, Denmark)
- Diabetes Wellness Network Sweden
- Swedish Diabetes Foundation
- Petrus and Augusta Hedlunds Foundation (Stockholm, Sweden)
- Ake Wiberg Foundation (Boras, Sweden)
- Adlerbert Research Foundation (Gothenburg, Sweden)
- M. Bergvall Foundation (Stockholm, Sweden)
- Novo Nordisk Fonden [NNF14OC0010799, NNF14OC0009667] Funding Source: researchfish
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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 beta-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 beta-oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.
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