The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.

Protective Effects of Individual and Combined Low Dose Beta-Carotene and Metformin Treatments against High-Fat Diet-Induced Responses in Mice

“…In order to investigate possible mechanisms underlying changes in total liver lipid content, hepatic expression levels of genes related to fatty acid catabolism ( Cpt1a , Ppara , Ppargc1a ), fatty acid and triacylglycerol synthesis ( Gck, Fasn , Gpat , Srebf1 ) and autophagy ( Becn1 , Atg7, Map1lc3b , Foxo3a ) were analyzed ( Figure 6 B). The latter was included because autophagy of lipid droplets (lipophagy) is increasingly recognized to contribute to decreased hepatic steatosis [ 39 ]. HFD feeding induced an upregulation of the hepatic expression of Atg7 that was maximal and statistically significant in the BC+MET group.…”

Posidonia oceanica (L.) Delile Extract Reduces Lipid Accumulation through Autophagy Activation in HepG2 Cells

“…Autophagy may then regulate hepatocellular lipid accumulation through selective degradation of cellular lipid stores (lipophagy). However, large or chronic lipid exposure tends to deregulate the autophagy process [13,[16][17][18]. Accumulating evidence suggests that impaired autophagy prevents the clearance of LDs, damaged mitochondria, and toxic protein aggregates, which can be produced during the progression of various liver diseases, thus contributing to the development of steatosis, steatohepatitis, fibrosis, and cancer [19,20].…”

Association between apolipoprotein E gene polymorphism and nonalcoholic fatty liver disease in Southern China: A case‐control study

“…Recent studies reveal that NAFLD was associated with lipid disorders. [8][9][10] The disruption of the lipid metabolism balance in the liver leads to lipid accumulation, which in turn causes liver toxicity and NAFLD. 11 Dyslipidemia is characterized by elevated levels of free fatty acids, low-density lipoprotein-cholesterol (LDL-c) and triglycerides (TG), or reduced levels of high-density lipoprotein-cholesterol (HDLc).…”

“…Recent studies reveal that NAFLD was associated with lipid disorders. 8 , 9 , 10 The disruption of the lipid metabolism balance in the liver leads to lipid accumulation, which in turn causes liver toxicity and NAFLD. 11 …”