scholarly journals Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Tulasi Yadati ◽  
Tom Houben ◽  
Albert Bitorina ◽  
Yvonne Oligschlaeger ◽  
Marion J. Gijbels ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Cathepsin D ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Label Free ◽  
Sprague Dawley ◽  
Knock Out ◽  
Hepatic Lipid ◽  
Metabolic Inflammation ◽  
Hepatic Lipid Accumulation

Background & AimsThe lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in Sprague-Dawley rats with steatosis. However, the individual roles of extracellular and intracellular CTSD in NASH are not yet known. In the current study, we evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors.MethodsLow-density lipoprotein receptor knock out (Ldlr-/-) mice were fed a high-fat, high cholesterol (HFC) diet for ten weeks to induce NASH. Further, to investigate the effects of CTSD inhibition, mice were injected either with an intracellular (GA-12) or extracellular (CTD-002) CTSD inhibitor or vehicle control at doses of 50 mg/kg body weight subcutaneously once in two days for ten weeks.ResultsLdlr-/- mice treated with extracellular CTSD inhibitor showed reduced hepatic lipid accumulation and an associated increase in faecal bile acid levels as compared to intracellular CTSD inhibitor-treated mice. Furthermore, in contrast to intracellular CTSD inhibition, extracellular CTSD inhibition switched the systemic immune status of the mice to an anti-inflammatory profile. In line, label-free mass spectrometry-based proteomics revealed that extra- and intracellular CTSD fractions modulate proteins belonging to distinct metabolic pathways.ConclusionWe have provided clinically translatable evidence that extracellular CTSD inhibition shows some beneficial metabolic and systemic inflammatory effects which are distinct from intracellular CTSD inhibition. Considering that intracellular CTSD inhibition is involved in essential physiological processes, specific inhibitors capable of blocking extracellular CTSD activity, can be promising and safe NASH drugs.

scholarly journals Sterol O-acyltransferase 2 chaperoned by apolipoprotein J facilitates hepatic lipid accumulation following viral and nutrient stresses

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hung-Yu Sun ◽  
Tzu-Ying Chen ◽  
Yu-Ching Tan ◽  
Chun-Hsiang Wang ◽  
Kung-Chia Young
Keyword(s):  
Cholesteryl Ester ◽  
Lipid Accumulation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Apolipoprotein J

AbstractThe risks of non-alcoholic fatty liver disease (NAFLD) include obese and non-obese stresses such as chronic hepatitis C virus (HCV) infection, but the regulatory determinants remain obscure. Apolipoprotein J (ApoJ) served as an ER-Golgi contact-site chaperone near lipid droplet (LD), facilitating HCV virion production. We hypothesized an interplay between hepatic ApoJ, cholesterol esterification and lipid deposit in response to NAFLD inducers. Exposures of HCV or free-fatty acids exhibited excess LDs along with increased ApoJ expression, whereas ApoJ silencing alleviated hepatic lipid accumulation. Both stresses could concomitantly disperse Golgi, induce closer ApoJ and sterol O-acyltransferase 2 (SOAT2) contacts via the N-terminal intrinsically disordered regions, and increase cholesteryl-ester. Furthermore, serum ApoJ correlated positively with cholesterol and low-density lipoprotein levels in normal glycaemic HCV patients, NAFLD patients and in mice with steatosis. Taken together, hepatic ApoJ might activate SOAT2 to supply cholesteryl-ester for lipid loads, thus providing a therapeutic target of stress-induced steatosis.

scholarly journals The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Abigail D. G. Nunn ◽  
Tullio Scopigno ◽  
Natalia Pediconi ◽  
Massimo Levrero ◽  
Henning Hagman ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Lipid Accumulation ◽  
Insulin Signalling ◽  
Lipid Synthesis ◽  
Label Free ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Sugar Levels ◽  
Droplet Morphology ◽  
Anti Stokes

Abstract Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome.

Corosolic Acid Attenuates Hepatic Lipid Accumulation and Inflammatory Response via AMPK/SREBPs and NF-κB/MAPK Signaling Pathways

2020 ◽  
Vol 48 (03) ◽  
pp. 579-595
Author(s):  
Jian-Xiu Zhang ◽  
Wei-Jun Feng ◽  
Guan-Cheng Liu ◽  
Qian-Qian Ma ◽  
Hai-Lan Li ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Density Lipoprotein ◽  
Mapk Signaling ◽  
Lipoprotein Cholesterol ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Corosolic Acid ◽  
Mapk Signaling Pathways

Corosolic acid (CA) is the main active component of Lagetstroemia speciosa and has been known to serve as several different pharmacological effects, such as antidiabetic, anti-oxidant, and anticancer effects. In this study, effects of CA on the hepatic lipid accumulation were examined using HepG2 cells and tyloxapol (TY)-induced hyperlipidemia ICR mice. CA significantly inhibited hepatic lipid accumulation via inhibition of SREBPs, and its target genes FAS, SCD1, and HMGCR transcription in HepG2 cells. These effects were mediated through activation of AMPK, and these effects were all abolished in the presence of compound C (CC, an AMPK inhibitor). In addition, CA clearly alleviated serum ALT, AST, TG, TC, low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) levels, and obviously attenuated TY-induced liver steatosis and inflammation. Moreover, CA significantly upregulated AMPK, ACC, LKB1 phosphorylation, and significantly inhibited lipin1, SREBPs, TNF-[Formula: see text], F4/80, caspase-1 expression, NF-[Formula: see text]B translocation, and MAPK activation in TY-induced hyperlipidemia mice. Our results suggest that CA is a potent antihyperlipidemia and antihepatic steatosis agent and the mechanism involved both lipogenesis and cholesterol synthesis and inflammation response inhibition via AMPK/SREBPs and NF-[Formula: see text]B/MAPK signaling pathways.

Electroacupuncture Attenuates Hepatic Lipid Accumulation via Amp-Activated Protein Kinase (Ampk) Activation in Obese Rats

2016 ◽  
Vol 34 (3) ◽  
pp. 209-214 ◽  
Author(s):  
Meirong Gong ◽  
Chen Cao ◽  
Fengli Chen ◽  
Qian Li ◽  
Xiaolin Bi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Total Cholesterol ◽  
Lipid Accumulation ◽  
Control Group ◽  
Sprague Dawley ◽  
Fat Pad ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

Background Electroacupuncture (EA) may offer an effective alternative approach for the treatment of obesity. EA mobilizes energy stores, but its effect on hepatic lipid metabolism is unknown, and the underlying mechanisms remain unclear. Objective To examine the effect of EA on hepatic lipid accumulation in diet-induced obese (DIO) rats, and to explore potential underlying mechanisms. Methods Male Sprague-Dawley rats were fed a normal diet (control group, n=10) or a high-fat diet (HFD) for 12 weeks to induce obesity. Those exhibiting diet-induced obesity were subdivided into two groups, one receiving EA (DIO+EA group, n=10) and one left untreated (DIO group, n=10) and observed for a further 4 weeks. Body, liver and fat pad weight were measured, and liver injury was assessed histologically as well as by measuring serum values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic triglyceride (TG) and total cholesterol were quantified by enzymatic colorimetric methods. Expression of liver AMP-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC), and carnitine palmitoyltransferase (CPT-1) was measured by Western blotting. Results EA treatment led to a reduction in body, liver and fat pad weight in DIO rats. This was accompanied by decreases in hepatic TG and total cholesterol values, fatty droplet accumulation, and serum concentrations of ALT and AST. Furthermore, EA treatment restored phosphorylation levels of AMPK (Thr172) and ACC (Ser79) inhibited by HFD, and increased CPT-1 expression. Conclusions EA reduces HFD-induced hepatic lipid accumulation, an effect that appears to be mediated through AMPK signalling pathways. Our results shed new light on the mechanisms by which EA may reduce obesity.

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