Inverse relationship between very low‐density lipoprotein (VLDL) ceramides, diacylglycerols, and triacylglycerols in human 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.

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PO4-93 MECHANISMS OF ACUTE ISCHEMIA-DEPENDENT MYOCARDIAL LIPID ACCUMULATION: A NOVEL ROLE FOR THE VERY-LOW-DENSITY-LIPOPROTEIN RECEPTOR

Atherosclerosis Supplements ◽

10.1016/s1567-5688(07)71103-0 ◽

2007 ◽

Vol 8 (1) ◽

pp. 40

Author(s):

J.C. Perman ◽

P. Boström ◽

M. Lindbom ◽

S-O. Olofsson ◽

J. Boren

Keyword(s):

Lipid Accumulation ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acute Ischemia ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Low Density Lipoprotein Receptor ◽

Density Lipoprotein Receptor

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

Communications Biology ◽

10.1038/s42003-021-02093-2 ◽

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.

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Dyslipidemia is the hallmark of the metabolic syndrome in postmenopausal women

Annals of Medical Physiology ◽

10.23921/amp.2020v4i2.115684 ◽

2020 ◽

Vol 4 (2) ◽

pp. 18-21

Author(s):

Asim Alaaeldin Osman ◽

Ahmed Mohamed Fadlalla

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Total Cholesterol ◽

Postmenopausal Women ◽

Lipid Accumulation ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Significant Negative Correlation ◽

Very Low Density Lipoprotein ◽

Low Density

The incidence of cardiovascular diseases (CVD) increases after menopause and may be due to changes in the plasma lipid-lipoprotein levels that occur following menopausal transition. Physiological estrogen withdrawal during menopause plays a major role in abnormal lipid metabolism such as elevated low-density lipoprotein concentration. The aim of this study was to determine the relationship between dyslipidemia and the causative factors of metabolic syndrome in postmenopausal women. In this cross-sectional study, 290 postmenopausal Sudanese women were included. Lipid profiles were measured by spectrophotometer, estrogen hormone determined by ELISA, insulin resistance determined by HOMA-2 calculator and lipid accumulation product was calculated by the following equation (waist circumference in cm X triglyceride concentration in mM). The results revealed that total cholesterol, triglycerides, low-density lipoprotein levels and very low-density lipoprotein levels were significantly higher in the postmenopausal women with metabolic syndrome (MS) in comparison to those without the MS. Elevated total cholesterol levels were seen in 51.7 %, elevated triglycerides were seen in 49.7% and elevated low-density lipoprotein levels were seen in 29.3% whereas reduced high density lipoprotein levels were seen in 16.89% of the postmenopausal women. Total cholesterol, triglycerides and very low-density lipoprotein values showed a significant positive correlation with insulin resistance and lipid accumulation and a significant negative correlation with the estrogen hormone level. In addition, high density lipoproteins showed a significant negative correlation with lipid accumulation levels.

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