Hepatic phospholipid remodeling in metabolic disorders

Tian, Ye

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https://hdl.handle.net/2142/121982 Copy

Description

Title

Hepatic phospholipid remodeling in metabolic disorders

Author(s)

Tian, Ye

Issue Date

2023-11-27

Director of Research (if dissertation) or Advisor (if thesis)

Wang, Bo

Doctoral Committee Chair(s)

Wang, Bo

Committee Member(s)

• Anakk, Sayeepriyadarshini
• Nelson, Erik R.
• Spinella, Michael J.

Department of Study

Comparative Biosciences

Discipline

VMS - Comparative Biosciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Phospholipid
• Insulin resistance
• Non-alcoholic steatohepatitis (NASH)
• Mitochondria
• Lipid metabolism

Abstract

Biological membrane is critical to various cellular functions and metabolic processes. Since the fluid-mosaic model of the lipid bilayer was proposed, myriad research investigated the interaction between membrane and proteins. However, the roles of phospholipid (PL), the main fabric of membrane, on pathophysiology have until recently remained unclear. Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome with growing impact on global health. Recent studies have reported that hepatic PL composition in human NAFLD patients was significantly altered, suggesting potential pathological role of membrane PL composition2,3. Fatty acyl composition of PLs in the liver is controlled by the Lands’ cycle where the fatty acyl chain in sn-2 site will be substituted preferentially with polyunsaturated fatty acids (PUFA) by lysophosphatidylcholine acyltransferases 3 (LPCAT3)4. Here, we show that the expression of LPCAT3 is dramatically suppressed in human NASH livers compared to controls. LPCAT3 expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes the development of both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency increases reactive oxygen species production, likely due to impaired mitochondrial homeostasis as demonstrated by reduced mitochondrial DNA content and fragmented mitochondrial morphology. Moreover, overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH, suggesting that manipulating LPCAT3 expression may be an effective therapeutic strategy for NASH. Interestingly, despite the promotion of NASH, mice with hepatic Lpcat3 depletion exhibited significantly reduced blood glucose level with improved systemic metabolism. We demonstrated that hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction and hepatic glucose production suppression, and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and energy metabolism. The dissociation between NASH and insulin resistance in Lpcat3 liver knockout mice recapitulated the phenotype of a subpopulation of NASH patients and shed light on the pathogenesis of metabolic disorders.

Graduation Semester

2023-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Ye Tian

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