Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet
| Autor: | Gavin Fredrickson, Fanta Barrow, Michael W. Lopresti, Douglas G. Mashek, Arnav S. Desai, Xavier S. Revelo, Breann Abernathy, Wenqi Cui |
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| Rok vydání: | 2021 |
| Předmět: |
Male
RNA-Seq RNA sequencing Biochemistry chemistry.chemical_compound Mice iWAT inguinal white adipose tissue Endocrinology Lipid droplet lipase/hepatic Nonalcoholic fatty liver disease CE cholesteryl ester Chemistry Kupffer cell LAL lysosomal acid lipase TEM transmission electron microscope Mo/MF monocyte-derived macrophage DE differentially expressed medicine.anatomical_structure dietary fat Cholesteryl ester lysosomal acid lipase Female medicine.symptom NK natural killer Research Article medicine.medical_specialty autophagy LD lipid droplet TAG triacylglycerol Inflammation QD415-436 liver Immune system Internal medicine NAFLD GO Gene Ontology medicine Animals KC Kupffer cell FPC fructose palmitate and cholesterol Triglyceride immune infiltration nutritional and metabolic diseases Cell Biology Sterol Esterase IPA ingenuity pathway analysis medicine.disease cholesterol/cell and tissue digestive system diseases Mice Inbred C57BL SFA saturated FA Disease Models Animal Diet Western NAFLD nonalcoholic fatty liver disease Steatosis |
| Zdroj: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100133-(2021) |
| ISSN: | 1539-7262 |
| Popis: | Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol levels and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (LAL), encoded by the gene LIPA, which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet would prevent the development of NAFLD. As expected, mice fed the Western diet exhibited numerous markers of NAFLD, including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the Western diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Overall, we found that hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD, suggesting that targeting LAL expression may not be a viable route to treat NAFLD in humans. |
| Databáze: | OpenAIRE |
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