Lipophagy and liver disease: New perspectives to better understanding and therapy

Zhang, Zili; Yao, Zhen; Chen, Yifan; Lei, Qian; Jiang, Shuoyi; Zhou, Jingyi; Shao, Jiangjuan; Chen, Anping; Zhang, Feng; Zheng, Shizhong

doi:10.1016/j.biopha.2017.07.168

Cited by 54 publications

(31 citation statements)

References 89 publications

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“…Actually, the chronic overload of lipids has harmful effects in the liver, exposing resident hepatocytes to their cytotoxic action (lipotoxicity) and oxidative stress, the effect of which are more pronounced with aging (Zelber-Sagi et al, 2006;Chen et al, 2013;Xu et al, 2013a). Lipophagy represents the main lipid degrading system in the liver and its impairment was recently associated with the pathogenesis of NAFLD (Sinha et al, 2014;Zhang et al, 2018). In lipophagy, the neutral lipids are partially subtracted in autophagosomes and transported to lysosomes, which represent the final destination of lipids in this pathway.…”

Section: Discussionmentioning

confidence: 99%

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is associated with aging and features of metabolic syndrome. Lipotoxicity and oxidative stress are consequent to dysregulation of lipid metabolism and lipid accumulation, leading to hepatocyte injury and inflammation. Lipophagy consists in selective degradation of intracellular lipid droplets by lysosome and mounting evidence suggests that lipophagy is dysregulated in NAFLD. Here we demonstrate lipophagy impairment in experimental models of NAFLD and in a NAFLD patient cohort by histomorphological and molecular analysis. High fat diet-fed C57BL/6J male mice and high-fat/high-glucose cultured Huh7 cells showed accumulation of both p62/SQSTM1 and LC3-II protein. In 59 NAFLD patients, lipid droplet-loaded lysosomes/lipolysosomes and p62/SQSTM1 clusters correlated with NAFLD activity score (NAS) and with NAS and fibrosis stage, respectively, and levels of expression of lysosomal genes, as well as autophagy-related genes, correlated with NAS and fibrosis stage. An increased amount of lipid droplets, lipolysosomes and autophagosomes was found in subjects with NAFLD compared to healthy subjects at ultrastructural level. In conclusion, here we observed that NAFLD is characterized by histological, ultrastructural and molecular features of altered autophagy that is associated with an impaired lipid degradation. Impaired autophagy is associated with features of advanced disease. Lipopolysosomes, as individuated with light microscopy, should be further assessed as markers of disease severity in NAFLD patients.

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Section: Discussionmentioning

confidence: 99%

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

et al. 2020

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“…Cellular regulation Metabolic effects References AKT -Growth regulation, metabolism control -Glucose metabolism: ↑ glucose transporters on cell surface → glycolysis -↓ FOXO1: ↓ gluconeogenesis -↑ PI3K/AKT/mTOR: biosynthesis of macromolecules -Insulin resistance: FOXO1 activation → ↓ AKT → hyperglycemia and phosphorylation of IRS-1, ↓ GLUT-4 translocation, ↓ glucose transported into cells -Caloric abundance: ↑ mTOR → ↑ lipid droplets Hirata et al, 2018;Józwiak, Forma, Brys, & Krzeslak, 2014;Manning & Toker, 2017;Semenkovich, Goldberg, & Goldberg, 2016;Welty, Alfaddagh, & Elajami, 2016;Zhang et al, 2018 AMPK -↑ demand for energy or caloric restriction: ↓ ATP → ↑ AMP/ATP -SIRT1 acetylation: simulates a caloric depleted state → AMPK activation → ↓ de novo lipogenesis and ↑ insulin sensitivity, lipolysis, and mitochondrial fatty acid (FA) oxidation -TSH → AMPK: ↓ HMG-CoAR and ↓ cholesterol synthesis -↓ insulin sensitivity: ↓ AMPK, defective autophagy and ROS generation -Starvation: ↑ autophagy, to ↑ nutrients available to cells → ↑ ULK1 and mTORC1 -AMPK improves NASH induced by highfat-diet: suppression of several key lipogenic factors, such as SREBP-1 (↓ triglyceride synthesis), HMG-CoAR, cholesterol synthesis; and ↑ ACC:…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Central cellular signaling pathways involved with the regulation of lipid metabolism in the liver: a review

Lopes

Santana

Cruz

et al. 2020

Acta Sci. Biol. Sci.

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The liver is primarily responsible for energy homeostasis and the regulation of lipid, carbohydrate and protein metabolism. Lipid metabolism consists of distributing lipids to peripheral tissues or ensuring their return to the liver to be reprocessed. Additionally, cellular metabolism is regulated by several molecules in different signaling pathways. Lipid homeostasis in the liver is mainly regulated by AKT, AMPK, SREBP, PPAR, and JNK. The PI3K/AKT/mTOR signaling pathway results in the biosynthesis of macromolecules and regulates lipogenesis and the expression of lipogenic genes. AMPK is an energy sensor that regulates metabolism and is activated when stored ATP is depleted, and it is responsible for the suppression of several key lipogenic factors in the liver related to cholesterol and fatty acid synthesis. SREBPs control lipogenic gene expression and cholesterol metabolism and act in the nutritional regulation of fatty acids and triglycerides. The continued activation of SREBPs is associated with cellular stress, inflammation and ultimately steatosis. PPARs are intrinsically important regulators of lipid metabolism. These genes are essential to various metabolic processes, especially lipid and glucose homeostasis, and can play a role in cell differentiation. JNK signaling is related to insulin resistance and its activation results in decreased mitochondrial activity and fat accumulation. Therefore, the study of cell signaling pathways related to lipid metabolism and liver function may help to identify abnormalities and develop strategies to manage and regulate metabolic disorders and resulting complications.

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“…These data suggest disruption of autophagy activation in maternal HFD livers, compromising its beneficial effects in removing damaged organelles and proteins. Besides that, disruption of autophagy pathways could contribute to hepatic lipid deposition because some lipid droplets are removed from the liver by the lysosomal pathway of autophagy, a process termed lipophagy …”

Section: Resultsmentioning

confidence: 99%

Differentiated Hepatic Response to Fructose Intake during Adolescence Reveals the Increased Susceptibility to Non‐Alcoholic Fatty Liver Disease of Maternal High‐Fat Diet Male Rat Offspring

Oliveira

Caetano

Miranda

et al. 2020

Molecular Nutrition Food Res

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Scope: Non-alcoholic fatty liver disease (NAFLD) among adolescents has been related to fructose intake. Additionally, maternal high-fat diet (mHFD) increases the offspring susceptibility to NAFLD at adulthood. Here, it is hypothesized that mHFD may exacerbate the fructose impact in adolescent male rat offspring, by changing the response of contributing mechanisms to liver injury. Methods and results: Female Wistar rats receive standard (mSTD: 9% fat) or high-fat diet (mHFD: 29% fat) prior mating throughout pregnancy and lactation. After weaning, offspring receive standard chow and, from the 25th to 45th day, receive water or fructose-drinking water (15%). At 46 days old, fructose groups show increased adiposity, increased serum and hepatic triglycerides, regardless of maternal diet. Fructose aggravates the hepatic imbalance of redox state already exhibited by mHFD offspring. The hepatic activation of cellular repair pathways by fructose, such as unfolded protein response and macroautophagy, is disrupted only in mHFD offspring. Fructose does not change the liver morphology of mSTD offspring. However, it intensifies the liver injury already present in mHFD offspring.

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Lipophagy and liver disease: New perspectives to better understanding and therapy

Cited by 54 publications

References 89 publications

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Central cellular signaling pathways involved with the regulation of lipid metabolism in the liver: a review

Differentiated Hepatic Response to Fructose Intake during Adolescence Reveals the Increased Susceptibility to Non‐Alcoholic Fatty Liver Disease of Maternal High‐Fat Diet Male Rat Offspring

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