Autophagy in Hepatic Steatosis: A Structured Review

Abstract

Steatosis is the accumulation of neutral lipids in the cytoplasm. In the liver, it is associated with overeating and a sedentary lifestyle, but may also be a result of xenobiotic toxicity and genetics. Non-alcoholic fatty liver disease (NAFLD) defines an array of liver conditions varying from simple steatosis to inflammation and fibrosis. Over the last years, autophagic processes have been shown to be directly associated with the development and progression of these conditions. However, the precise role of autophagy in steatosis development is still unclear. Specifically, autophagy is necessary for the regulation of basic metabolism in hepatocytes, such as glycogenolysis and gluconeogenesis, response to insulin and glucagon signaling, and cellular responses to free amino acid contents. Also, genetic knockout models for autophagy-related proteins suggest a critical relationship between autophagy and hepatic lipid metabolism, but some results are still ambiguous. While autophagy may seem necessary to support lipid oxidation in some contexts, other evidence suggests that autophagic activity can lead to lipid accumulation instead. This structured literature review aims to critically discuss, compare, and organize results over the last 10 years regarding rodent steatosis models that measured several autophagy markers, with genetic and pharmacological interventions that may help elucidate the molecular mechanisms involved.

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

“…Autophagy is an evolutionarily conserved intracellular degradative process that regulates metabolism and maintains cellular homeostasis by removing aggregated, damaged and/or misfolded proteins, and damaged organelles through cytosolic sequestration and subsequent lysosomal degradation [11]. In the light of this, it is known that a deficiency in autophagy could contribute to the development or progression of several disease conditions, including non-alcoholic fatty liver disease (NAFLD) [12,13]. NAFLD is the most common liver disease in Western countries and is defined as evidence of hepatic steatosis without any cause of secondary hepatic fat accumulation, such as alcohol abuse, use of steatogenic drugs, or inherited disorders [14].…”

“…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].…”

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

“…One of the first reports of autophagy in the liver during NAFLD was by Singh and colleagues in 2009 (Singh et al, 2009). Since then hundreds of papers have been written on the subject, of which several reviews of note (Flessa et al, 2021;Wu et al, 2018;Ramos et al, 2021). In this seminal paper, Singh et al demonstrated in both in vitro and in vivo settings that the inhibition of autophagy led to increased lipid accumulation, reduced β-oxidation, and reduced VLDL secretion in hepatocytes coining the term "macrolipophagy".…”

Cytoskeleton alterations in non-alcoholic fatty liver disease

“…A NAFLD mouse model has shown impaired autophagy and enhanced conversion of LC3-I to LC3-II 66 , which was also observed in the livers of rats fed with a high fat and high cholesterol diet 67 . The excess of LC3-II suggests autophagosome accumulation in hepatic cells, which could in part explain the autophagy deficiency observed in NAFLD 68 . Therefore, the cytoskeleton could also be involved in such a deficiency, through LC3-II attachment to microtubules.…”