Regulation of Liver Metabolism by Autophagy

Abstract

Intracellular components must be recycled for cells to maintain energy and ensure quality control of proteins and organelles. Autophagy is a highly conserved recycling process that involves degradation of cellular constituents in lysosomes. Although autophagy regulates a number of cell functions, it was first found to maintain energy balance in liver cells. As our understanding of autophagy has increased, we have found its connections to energy regulation in liver cells to be tight and complex. We review three mechanisms by which hepatic autophagy monitors and regulates cellular metabolism. Autophagy provides essential components (amino acids, lipids and carbohydrates) required to meet the cell’s energy needs, and it also regulates energy supply by controlling the number, quality, and dynamics of the mitochondria. Lastly, autophagy also modulates levels of enzymes in metabolic pathways. In light of the multiple ways in which autophagy participates to control liver metabolism, it is no surprise that dysregulation of autophagy has been associated with metabolic diseases such as obesity, diabetes, or metabolic syndrome, as well as liver-specific disorders such as fatty liver, non-alcoholic steatohepatitis and hepatocellular carcinoma. We discuss some of these connections and how hepatic autophagy might serve as a therapeutic target in common metabolic disorders.

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

“…It is possible that reduced overall protein synthesis/ubiquitination contributes to their lower abundance in CR, but we propose that, at least in some species and sex, increased autophagy could be behind the CR-induced proteostasis changes. Beyond its role in protein homeostasis, autophagy has been proven essential for specific adaptation to nutritional availability, both during nutrient excess and scarcity (Madrigal-Matute and Cuervo, 2016). Interestingly, TXNIP has also a role in stress-induced macroautophagy (Qiao et al, 2015), one of the hallmarks of aging.…”

“…Although CR increased overall autophagic activity in most of the experimental groups, we found marked sex and strain differences in the intensity of this autophagic response and the type of autophagy preferentially induced. Both macroautophagy and chaperone-mediated autophagy contribute to regulate hepatic metabolism but through different mechanisms (Madrigal-Matute and Cuervo, 2016). Macroautophagy directly mobilizes energy stores, such as lipid droplets, and also regulates metabolic flux by controlling mitochondria abundance through mitophagy.…”

Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame

“…ALD is a highly conserved eukaryotic process, once thought to involve the bulk degradation of senescent, long-lived proteins/organelles as well as cytosolic components following starvation (Mizushima et al, 2008; Klionsky et al, 2010; Rabinowitz & White, 2010; Cuervo, 2011; Rubinsztein et al, 2012). It is now recognized to be both a rather tightly regulated and selective process entailing macroautophagy with subsequent lysosomal degradation (Mizushima et al, 2008; Yang & Klionsky, 2009; Klionsky et al, 2010; Mizushima et al, 2010; Rabinowitz & White, 2010; Cuervo, 2011; Rubinsztein et al, 2012; Ohsumi, 2014; Madrigal-Matute & Cuervo, 2015; Bento et al, 2016; Wen & Klionsky, 2016). Macroautophagy (or autophagy for short) involves the concerted function of over 35 a u t ophagy-related g enes (ATGs; Mizushima et al, 2008; Yang & Klionsky, 2009; Klionsky et al, 2010; Mizushima et al, 2010; Rabinowitz & White, 2010; Cuervo, 2011; Rubinsztein et al, 2012; Ohsumi, 2014; Madrigal-Matute & Cuervo, 2015; Bento et al, 2016; Wen & Klionsky, 2016) that generate multiprotein complexes that act cooperatively and sequentially to deliver the cargo for lysosomal degradation (Fig.…”

MicroRNA-141 Targets Sirt1 and Inhibits Autophagy to Reduce HBV Replication

“…Further, the autophagic flux experiment confirmed the autophagy inhibition of miR-141. Autophagy, which was discovered in the liver, is a highly conserved recycling process regulating a number of cell functions including liver metabolism [32, 33]. The pathogenesis of various hepatic diseases (including viral hepatitis, hepatocellular carcinoma, and fatty liver) involved the dysregulation of autophagy [34, 35].…”