Shuo Y Ma1,2, Ke S Sun1,2, Miao Zhang1,2, Xia Zhou1,2, Xiao H Zheng1,2, Si Y Tian1,2, Yan S Liu1,2, Ling Chen3, Xing Gao4, Jing Ye4, Xin M Zhou1,2, Jing B Wang1,2, Ying Han1,2. 1. Division of Hepatology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. 2. State Key Laboratory of Cancer Biology, National Clinical Research Centre for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. 3. Division of Pathology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. 4. Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Abstract
BACKGROUND & AIMS: The pathological hallmark of nonalcoholic fatty liver disease (NAFLD) is an imbalance in hepatic lipid homeostasis, in which lipophagy has been found to play a vital role. However, the underlying molecular mechanisms remain unclear. We investigated the role of chaperone-mediated autophagy (CMA) in the pathogenesis of NAFLD. METHODS: CMA activity was evaluated in liver tissues from NAFLD patients and high-fat diet (HFD)-fed mice. Liver-specific LAMP2A-knockout mice and HepG2 cells lacking LAMP2A [L2A(-) cells] were used to investigate the influence of CMA on lipolysis in hepatocytes. The expression of Plin5, a lipid droplet (LD)-related protein, was also evaluated in human and mouse liver tissues and in [L2A(-)] cells. RESULTS: Here, we found disrupted CMA function in the livers of NAFLD patients and animal models, displaying obvious reduction of LAMP2A and concurrent with decreased levels of CMA-positive regulators. More LDs and higher serum triglycerides accumulated in liver-specific LAMP2A-knockout mice and L2A(-) cells under high-fat challenge. Meanwhile, deleting LAMP2A hindered LD breakdown but not increased LD formation. In addition, the LD-associated protein Plin5 is a CMA substrate, and its degradation through CMA is required for LD breakdown. CONCLUSIONS: We propose that the disruption of CMA-induced Plin5 degradation obstacles LD breakdown, explaining the lipid homeostasis imbalance in NAFLD.
BACKGROUND & AIMS: The pathological hallmark of nonalcoholic fatty liver disease (NAFLD) is an imbalance in hepatic lipid homeostasis, in which lipophagy has been found to play a vital role. However, the underlying molecular mechanisms remain unclear. We investigated the role of chaperone-mediated autophagy (CMA) in the pathogenesis of NAFLD. METHODS: CMA activity was evaluated in liver tissues from NAFLD patients and high-fat diet (HFD)-fed mice. Liver-specific LAMP2A-knockout mice and HepG2 cells lacking LAMP2A [L2A(-) cells] were used to investigate the influence of CMA on lipolysis in hepatocytes. The expression of Plin5, a lipid droplet (LD)-related protein, was also evaluated in human and mouse liver tissues and in [L2A(-)] cells. RESULTS: Here, we found disrupted CMA function in the livers of NAFLD patients and animal models, displaying obvious reduction of LAMP2A and concurrent with decreased levels of CMA-positive regulators. More LDs and higher serum triglycerides accumulated in liver-specific LAMP2A-knockout mice and L2A(-) cells under high-fat challenge. Meanwhile, deleting LAMP2A hindered LD breakdown but not increased LD formation. In addition, the LD-associated protein Plin5 is a CMA substrate, and its degradation through CMA is required for LD breakdown. CONCLUSIONS: We propose that the disruption of CMA-induced Plin5 degradation obstacles LD breakdown, explaining the lipid homeostasis imbalance in NAFLD.
Authors: Aldo Grefhorst; Ivo P van de Peppel; Lars E Larsen; Johan W Jonker; Adriaan G Holleboom Journal: Front Endocrinol (Lausanne) Date: 2021-02-01 Impact factor: 5.555
Authors: Claudio M Fader Kaiser; Patricia S Romano; M Cristina Vanrell; Cristian A Pocognoni; Julieta Jacob; Benjamín Caruso; Laura R Delgui Journal: Front Cell Dev Biol Date: 2022-02-07