Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane

Abstract

Ceramide and diacylglycerol (DAG) are bioactive lipids and mediate many cellular signaling pathways. Sphingomyelin synthase (SMS) is the single metabolic link between the two, while SMS2 is the only SMS form located at the plasma membrane. SMS2 functions were investigated in HepG2 cell lines stably expressing SMS2. SMS2 overexpression did not alter sphingomyelin (SM), phosphatidylcholine (PC), or ceramide levels. DAG content increased by approx. 40% and led to downregulation of DAG-dependent protein kinase C (PKC). SMS2 overexpression also induced senescence, characterized by positivity for β-galactosidase activity and heterochromatin foci. HepG2-SMS2 cells exhibited protruded mitochondria and suppressed mitochondrial respiration rates. ATP production and the abundance of Complex V were substantially lower in HepG2-SMS2 cells as compared to controls. SMS2 overexpression was associated with inflammasome activation based on increases in IL-1β and nlpr3 mRNA levels. HepG2-SMS2 cells exhibited lipid droplet accumulation, constitutive activation of AMPK based on elevated 172Thr phosphorylation, increased AMPK abundance, and insensitivity to insulin suppression of AMPK. Thus, our results show that SMS2 regulates DAG homeostasis and signaling in hepatocytes and also provide proof of principle for the concept that offset in bioactive lipids’ production at the plasma membrane can drive the senescence program in association with steatosis and, seemingly, by cell-autonomous mechanisms.

Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression

“…The senescent HepG2 cell gene signature has been shown to be highly comparable to human chronic liver diseases such as non-alcoholic fatty liver disease, alcohol-related liver disease and hepatitis C related liver disease [ 18 ]. Further, senescent HepG2 cell models have also been used successfully to explore the pathophysiology of chronic liver disease [ 19 , 22 , 23 ]. The above detailed evidence validates and supports the use of senescent HepG2 cell models for the understanding of human chronic liver disease.…”

Вікові Зміни У Сфінголіпідному Складі Тканин Цнс Та Поведінкових Реакціях Щурів І Їх Модуляція Дієтами Збагаченими Жирами Різної Насиченості

“…Дієти, насичені різними типами ЖК спричиняють функціональні зміни внутрішніх органів. Дієти з підвищеним вмістом НЖК можуть інтенсифікувати запальні процеси у тканинах та викликати функціональні порушення органів ЦНС (Deevska et al, 2021). Навпаки, включення до раціону ПНЖК може зменшувати інтенсивність запальних процесів в мозку (Daily et al, 2021).…”

Formononetin Inhibits Hepatic I/R-Induced Injury through Regulating PHB2/PINK1/Parkin Pathway

“…Liver is the largest organ in the human body and plays important role in regulating the body's metabolic. These processes consume huge amounts of energy which produced by mitochondria from oxygen and glycolipids [5]. When liver is subjected to ischemia and hypoxia, the mitochondria function is destroyed, and the hepatic functions are damaged [6].…”