Autophagy Deficiency by Hepatic FIP200 Deletion Uncouples Steatosis From Liver Injury in NAFLD

Abstract

Nonalcoholic fatty liver disease is a metabolic disorder commonly associated with obesity. A subset of nonalcoholic fatty liver disease patients further develops nonalcoholic steatohepatitis that is characterized by chronic liver injury, inflammation, and fibrosis. Recent work has implicated the autophagy pathway in the mobilization and oxidation of triglycerides from lipid droplets. However, whether impaired autophagy in hepatocytes drives excess fat accumulation in the liver remains controversial. In addition, the role of autophagy in protecting the liver from gut endotoxin-induced injury has not been elucidated. Here we generated mice with liver-specific autophagy deficiency by the conditional deletion of focal adhesion kinase family kinase-interacting protein of 200 kDa (also called Rb1cc1), a core subunit of the mammalian autophagy related 1 complex. To our surprise, mice lacking FIP200 in hepatocytes were protected from starvation- and high-fat diet-induced fat accumulation in the liver and had decreased expression of genes involved in lipid metabolism. Activation of the de novo lipogenic program by liver X receptor was impaired in FIP200-deficient livers. Furthermore, liver autophagy was stimulated by exposure to low doses of lipopolysaccharides and its deficiency-sensitized mice to endotoxin-induced liver injury. Together these studies demonstrate that hepatocyte-specific autophagy deficiency per se does not exacerbate hepatic steatosis. Instead, autophagy may play a protective role in the liver after exposure to gut-derived endotoxins and its blockade may accelerate nonalcoholic steatohepatitis progression.

Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes

“…Autophagy knockout in pancreatic b-cells leads to decreased b-cell mass and hyperglycaemia 5,6 . In contrast, autophagy knockout in insulin target tissues such as skeletal muscle or liver leads to enhanced insulin sensitivity and reduced lipid injury 11,46 probably because of the release of FGF21 as a consequence of mitochondrial stress 11 , while dissimilar results have also been reported 8,30 . Autophagy knockout in adipose tissue also leads to protection from diet-induced obesity and insulin resistance together with impaired adipocyte differentiation 7,9 .…”

ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis

“…While further understanding is needed as to how ASMase regulates ER Ca 2+ homeostasis, our findings showing hepatic steatosis resistance despite autophagy impairment are in agreement with recent findings. Mice with liver-specific deletion of FIP200, a core subunit of the Atg1 complex, were protected from starvation and HFDinduced hepatic steatosis [37]. Importantly, FIP200 mutant mice exhibited defective diet-induced activation of lipogenic pathways.…”

Acid sphingomyelinase-ceramide system in steatohepatitis: A novel target regulating multiple pathways

“…For instance, Atg7 Dhep mice, fed a HFD, have a reduced hepatic lipid content [43]. Moreover, mice with liver-specific deletion of FIP200, a core subunit of the Atg1 complex, are protected from starvation and HFD-induced hepatic steatosis [44]. The view of autophagy as a lipogenic mechanism is also supported by the role of fasting in both processes.…”