Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress‐related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

Obese visceral fat tissue inflammation: from protective to detrimental?

“…Loss of metabolic homeostasis and tissue damage is accompanied by activation of the resident immune system. Pro-inflammatory responses are carried by Kupffer cells, stellate cells, many infiltrated immune cell types, other stromal cell types, and also by hepatocytes [129][130][131][132][133][134][135][136]. In animal models, immune intervention trials often have led to improved metabolic control with or without decreased adiposity indicating a pathogenic role of inflammatory immune reactivity [137][138][139].…”

The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

“…Dysfunction of hepatocyte endoplasmic reticulum (ER) homeostasis and the disturbance of its interaction with mitochondria also play an important role in NAFLD pathophysiology. The ER uses the unfolded protein response pathway to maintain protein and lipid homeostasis whenever exposed to hyperlipidemia, insulin resistance, inflammation, drugs, or other disturbances ( Flessa et al, 2022 ).…”

AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats

“…The combined action of the PERK/IRE-1α/ATF6 pathways leads to either recovery from ER stress or progression to hepatic steatosis and steatohepatitis. Targeting these pathways has been proven to halt NAFLD progression [ 2 , 11 , 12 ].…”

“…Hepatic ER stress and UPR induction of the PERK/IRE-1α/ATF6 pathways induce oxidative stress, generates ROS, and promotes hepatic fatty changes [ 12 ]. These in turn trigger a variety of stress-sensitive intracellular signaling pathways, primarily NF-κB.…”