Non-parenchymal hepatic cell lipotoxicity and the coordinated progression of non-alcoholic fatty liver disease and atherosclerosis

Abstract

Purpose of reviewNon-alcoholic fatty liver disease (NAFLD) appears to be independently associated with the development of atherosclerosis. The biological mechanisms underlying this association are complex, and likely involve liver-resident cell types other than hepatocytes. Thus, we review recent evidence that non-parenchymal hepatic cell responses to lipid excess contribute to the pathogenesis of both NAFLD and atherosclerosis.Recent findingsSignificant independent associations between NAFLD and atherosclerosis have been identified through cross-sectional studies and meta-analyses. Mechanistic studies in cell cultures and in rodent models suggest that liver-resident macrophages, activated hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) mount lipotoxic responses under NAFLD conditions which can contribute to the progression of both NAFLD and atherosclerosis.SummaryNon-parenchymal hepatic cell types exhibit some similarity in their responses to lipid excess, and in their pathogenic mechanisms, which likely contribute to the coordinated progression of NAFLD and atherosclerosis. In response to lipotoxic conditions, macrophages, Kupffer cells and HSC initiate robust inflammatory responses, whereas LSEC generate excess reactive oxygen species (ROS). The extent to which inflammatory cytokines and ROS produced by non-parenchymal cells contribute to the progression of both NAFLD and atherosclerosis warrants further investigation.

Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity

“…However, metabolic dysfunction associated with obesity and hepatic steatosis can result in a state of hepatocyte lipotoxicity. (17) To recapitulate this in vitro, we chronically (48 hours) treated hepatocytes with a mixture of palmitate and oleate (2:3, 0.5 mM) that has been thought to be representative of the most abundant FAs exposed to the liver in vivo, as well as palmitate and oleate in isolation, both at 0.5 mM. Following incubation, we observed a slight decrease in cell viability with FA treatments, which was more pronounced in the palmitate-containing treatments (Supporting Fig.…”

“…It is well documented that hepatic exposure to high and chronic levels of saturated FAs leads to ER stress, leading to metabolic dysfunction and induction of cell death pathways. (17) We reasoned that palmitateinduced reductions in choline uptake, CTL1, and choline incorporation into PC might be due to palmitate-induced ER stress. To test this, we used the well-known inducer of ER stress, tunicamycin, (21) which only slightly reduced cell viability at the higher dose (Supporting Fig.…”

“…Given the discordance between CTL1 transcript and protein expression in lean and obese livers, we next sought to determine whether CTL1 mRNA was translationally repressed. We performed polysome fractionation on lean and obese livers, and the mRNA distribution of Slc44a1 and a housekeeping control (Hprt, the gene encoding hypoxanthine-guanine phosphoribosyltransferase) were assessed across the fractions representing free mRNA (fractions 7-10), monosome (fractions 11-12), light polysome (fractions [13][14][15], and heavy polysome (fractions [16][17][18][19]. In line with a diminished protein content, in the livers of obese mice, we observed that Slc44a1, but not Hprt, was shifted toward the monosome fractions and away from the heavy polysome fractions, as compared with lean controls (Fig.…”

Fatty acid-induced lipotoxicity inhibits choline metabolism independent of ER stress in mouse primary hepatocytes

“…It is well documented that hepatic exposure to high and chronic levels of saturated FA leads to ER stress leading to metabolic dysfunction and induction of cell death pathways (21). We reasoned that palmitate-induced reductions in choline uptake, CTL1 and choline incorporation into PC might be due to palmitate-induced ER stress.…”

“…The liver is a dynamic metabolic organ that under normal, healthy conditions, functions to balance lipid synthesis, uptake and efflux. However, metabolic dysfunction associated with obesity and hepatic steatosis can result in a state of hepatocyte lipotoxicity (21). To recapitulate this in vitro, we chronically (48 h) treated hepatocytes with a mixture of palmitate and oleate (2:3, 0.5 mM) that has been thought to be representative of the most abundant FA exposed to the liver in vivo, as well as palmitate and oleate in isolation, both at 0.5 mM.…”