Anarchy in the UPR: A Ca²⁺-insensitive PKC inhibits SERCA activity to promote ER stress

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in Western countries, and is linked to the development of liver cancer and Type 2 diabetes (T2D). It is strongly associated with obesity, but the dysregulation of liver lipid storage is not fully understood. Fatty acid oversupply to hepatocytes can establish a vicious cycle involving diminished protein folding, endoplasmic reticulum (ER) stress, insulin resistance and further lipogenesis. This commentary discusses the recent findings of Lai et al. published in Bioscience Reports, that implicate protein kinase C delta (PKCδ) activation by fatty acids in the inhibition of the SERCA Ca²⁺ pump, resulting in reduced ER Ca²⁺ loading and protein misfolding. PKCδ therefore represents a target for the treatment of both steatosis and insulin resistance, key to the prevention of NAFLD and T2D.