Lipoprotein Lipase Up‐regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice

Abstract

Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)–specific LPL‐knockout (LplHSC‐KO) mice, LPL‐floxed (Lplfl/fl) mice, or double‐mutant toll‐like receptor 4–deficient (Tlr4−/−) LplHSC‐KO mice were fed a high‐fat/high‐cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high‐fat/high‐cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity‐related factors, such as free fatty acid, leptin, and interleukin‐6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC‐KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL‐mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL‐mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease

“…KCs were isolated from 6–8-week-old male C57BL6 mice using a 2-step Percoll gradient [25%/50% (vol/vol)] centrifugation method as described previously 23 , 24 and cultured in DMEM media containing 10% FBS and 1% penicillin-streptomycin. For characterisation, cells were fixed, stained with F4/80-Alexa 488 antibody (Bio-Rad, Hercules, CA, USA), mounted with a mounting medium containing DAPI, and visualised with a fluorescent microscope (Eclipse 80i, Nikon).…”

How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

“…With regards to the role of lipases, loss-of-function studies on hepatic lipase and LPL in the liver showed that knockout of hepatic lipase resulted in increased hepatic steatosis and inflammation in mice fed a high-fat high-cholesterol diet that might be due to the activation of stress pathways like SAPK/JNK and p38 [ 26 ]. LPL is mainly expressed in non-parenchymal cells in the liver and is also involved in hepatic fibrogenesis [ 27 ].…”

Extra virgin olive oil improved body weight and insulin sensitivity in high fat diet-induced obese LDLr−/−.Leiden mice without attenuation of steatohepatitis

“…Therefore, LPL regulation is a crucial component in hepatic lipid homeostasis. It has been shown, that as human NAFLD progresses, Lpl expression is elevated, specifically in HSCs 44 . Col1a1 and Mmp2 are genes involved in fibrosis processes.…”