Low-density Lipoprotein Receptor Deficiency Increases Susceptibility to Diet-induced Non-alcoholic Fatty Liver Disease in Mice
Sou Hyun Kim*,†, RanJu Woo*,†, Maziyar Veisi*,†, Mi Ran Byun**, Dae Youn Hwang***, Joung-Hee Kim****,#, and Young-Suk Jung*,#
*Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University
**Department of Pharmacy, Daegu Catholic University
***Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University
****Department of Medical Beauty Care, Dongguk University Wise
**Department of Pharmacy, Daegu Catholic University
***Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University
****Department of Medical Beauty Care, Dongguk University Wise
Correspondence to: #Joung-Hee Kim, Department of Medical Beauty Care, Dongguk University Wise, Gyeongju 38066, Korea
Tel: +82-54-770-2564, Fax: +82-54-770-2566
E-mail: 20230160@dogguk.ac.kr
Young-Suk Jung, College of Pharmacy, Pusan National University, Busan 46241, Korea
Tel: +82-51-510-2816, Fax: +82-51-513-6754
E-mail: youngjung@pusan.ac.kr
†These authors contributed equally to this work.
Tel: +82-54-770-2564, Fax: +82-54-770-2566
E-mail: 20230160@dogguk.ac.kr
Young-Suk Jung, College of Pharmacy, Pusan National University, Busan 46241, Korea
Tel: +82-51-510-2816, Fax: +82-51-513-6754
E-mail: youngjung@pusan.ac.kr
†These authors contributed equally to this work.
Received October 14, 2024; Revised October 24, 2024; Accepted December 5, 2024.
- Abstract
- Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized by hepatic inflammation, fibrosis and, potentially, cirrhosis. Lipid dysregulation plays a significant role in the exacerbation of liver fibrosis. This study investigated the impact of a fructose, palmitate, cholesterol, and trans-fat (FPC) diet on hepatic fibrosis in Ldlr-knockout (Ldlr KO) mice, a model with impaired cholesterol metabolism and elevated oxidized low-density lipoprotein. Ldlr KO mice on the FPC diet exhibited significantly slower increases in body weight and elevated serum ALT levels as compared to wild-type (WT) mice. Along with decreased high density lipoprotein cholesterol (HDL) levels, Ldlr KO mice also showed elevated serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and triglyceride (TG) levels, reflecting impaired cholesterol metabolism. Histopathological analysis revealed pronounced hepatocyte swelling, lipid accumulation, and more extensive fibrosis in Ldlr KO mice. TGF-β signaling pathway was notably activated in FPC-fed Ldlr KO mice, with increased levels of Smad2/3 and Smad4 proteins. Furthermore, α-SMA expression was elevated, reflecting active hepatic stellate cell activation and collagen deposition. As evidenced by elevated serum TC, LDL, and TG levels, the FPC diet significantly amplifies hepatic fibrosis in Ldlr KO mice by promoting lipid metabolism imbalance. Along with increased inflammatory responses and activation of the TGF-β signaling pathway, this lipid overload leads to enhanced collagen deposition and fibrosis. These findings highlight the critical role of cholesterol dysregulation and lipid imbalance in the progression of liver fibrosis, reinforcing the utility of Ldlr KO mice as a model for investigating NASH pathogenesis and developing potential therapeutic interventions.
- Keywords : Non-alcoholic fatty liver disease, Cholesterol metabolism, Low-density lipoprotein receptor, Liver fibrosis
- December 2024, 68 (6)
Full Text(PDF) Free- Social Network Service
-
- Services
- Cited By Articles
-
CrossRef (0)
Funding Information-
- Ministry of Food and Drug Safety
10.13039/501100003569
