The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis

Abstract

Macroautophagy/autophagy is a central mechanism by which cells maintain integrity and homeostasis, and endotoxin-induced autophagy plays important roles in innate immunity. Although TLR4 stimulation mediated by lipopolysaccharide (LPS) also upregulates autophagy in hepatocytes and liver, its physiological role remains elusive. The objective of this study was to determine the role of LPS-induced autophagy in the regulation of liver lipid metabolism. LPS treatment (5 mg/kg) increased autophagy, as detected by LC3 conversion and transmission electron microscopy (TEM) analysis in C57BL6 mouse livers. AC2F hepatocytes also showed increased autophagic flux after LPS treatment (1 μg/ml). To investigate the role of LPS-induced autophagy further, liver lipid metabolism changes in LPS-treated mice and fasted controls were compared. Interestingly, LPS-treated mice showed less lipid accumulation in liver than fasted mice despite increased fatty acid uptake and lipid synthesis-associated genes. In vitro analysis using AC2F hepatocytes demonstrated LPS-induced autophagy influenced the degradation of lipid droplets. Inhibition of LPS-induced autophagy using bafilomycin A or Atg7 knockdown significantly increased lipid accumulation in AC2F hepatocytes. In addition, pretreatment with chloroquine aggravated LPS-induced lipid accumulation and inflammation in C57BL6 mouse livers. The physiological importance of autophagy was verified in LPS-treated young and aged rats. Autophagic response was diminished in LPS-treated aged rats and lipid metabolism was impaired during sepsis, indicating autophagy response is important for regulating lipid metabolism after endotoxin challenge. Our findings demonstrate endotoxin-induced autophagy is important for the regulation of lipid metabolism, and suggest that autophagy helps maintain lipid metabolism homeostasis during sepsis.

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

“…Several drugs have been identified to distinguish each step in autophagic flux. For example, Torin1 and the mTOR inhibitor rapamycin can induce autophagy [22,23]. 3-Methyladenine (3-MA) blocks the formation of autophagosomes by inhibiting class III PI3K [24].…”

Effect of Icariside II and Metformin on Penile Erectile Function, Histological Structure, Mitochondrial Autophagy, Glucose-Lipid Metabolism, Angiotensin II and Sex Hormone in Type 2 Diabetic Rats With Erectile Dysfunction

“…Long-term disorders of glycolipid metabolism in patients with DM can cause pathological changes in the penile erectile tissue physiological functions and structure. 9,11,13 Decreased smooth muscle cell/collagen fibril proportions, endothelial dysfunction, increased apoptosis of CCSMCs and hypogonadism has been considered as the common pathological changes for T2DMED. 10,14 A long-term hyperglycemia state can accelerate the formation of HbA1c in patients with T2DM.…”

“…It had been reported that autophagy is a basic physiological process that helps maintain cell homeostasis, which has been shown to be involved in the pathological process of DMED. 13 Autophagy is at a low level under physiological conditions, and the degraded intracellular components can provide nutrients for cell recycling. 13,15 Mitochondrial autophagy is an adaptive metabolic response that is necessary to prevent increased levels of reactive oxygen species.…”

“…13 Autophagy is at a low level under physiological conditions, and the degraded intracellular components can provide nutrients for cell recycling. 13,15 Mitochondrial autophagy is an adaptive metabolic response that is necessary to prevent increased levels of reactive oxygen species. 15e17 However, autophagy acts on mitochondrial dysfunction when it is abnormally upregulated under pathological conditions.…”

Lipophagy in nonliver tissues and some related diseases: Pathogenic and therapeutic implications

“…Besides, studies have shown that lipophagy plays a vital role in bacterial infection (Josefsen et al, 2012). Bacteria endotoxin induces the occurrence of lipophagy during sepsis (Chung et al, 2017). Overall, lipophagy plays an important role in infectious diseases.…”