Dataset Information

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD.

ABSTRACT:

Background and aims

Nonalcoholic fatty liver disease (NAFLD) includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis. We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.

Methods

The effect of combined lipid-lowering drugs (statins and anti-PCSK9 monoclonal antibody) were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators, such as alarmins, responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress.

Results

Proteomic analysis revealed a number of proteins whose abundance was altered. They were components of metabolic pathways including fatty-acid degradation, glycolysis/gluconeogenesis, and nonalcoholic fatty liver disease. Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH: ubiquinone oxidoreductase. The expression of a majority of cytochromes (P4502E1, b5, and c) were up-regulated by lipid-lowering treatment. Long-term hyperlipidemic stress, even with a low-fat diet and lipid-lowering treatment, was accompanied by alarmin release (annexins, galectins, HSPs, HMGB1, S100 proteins, calreticulin, and fibronectin) that generated local inflammation and induced liver steatosis and aggressive fibrosis (by high abundance of galectin 3, fibronectin, and calreticulin).

Conclusions

The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent, combined lipid-lowering treatment with statin and inhibitor of PCSK9.

SUBMITTER: Ivan L

PROVIDER: S-EPMC9817060 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD.

Ivan Luminita L Uyy Elena E Suica Viorel I VI Boteanu Raluca M RM Cerveanu-Hogas Aurel A Hansen Rune R Antohe Felicia F

Journal of clinical and translational hepatology 20220714 2

<h4>Background and aims</h4>Nonalcoholic fatty liver disease (NAFLD) includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis. We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.<h4>Methods</h4>The effect of co ...[more]

PMID: 36643050

Similar Datasets

Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is defined by the abundance of lipid droplets (LDs) in hepatocytes. While historically considered simply depots for energy storage, LDs are increasingly recognized to impact a wide range of biological processes that influence cellular metabolism, signaling, and function. While progress has been made toward understanding the factors leading to LD accumulation (i.e. steatosis) and its progression to advanced stages of NAFLD and/or systemic metabolic dysfunction, much remains to be resolved.Scope of reviewThis review covers many facets of LD biology. We provide a brief overview of the major pathways of lipid accretion and degradation that contribute to steatosis and how they are altered in NAFLD. The major focus is on the relationship between LDs and cell function and the detailed mechanisms that couple or uncouple steatosis from the severity and progression of NAFLD and systemic comorbidities. The importance of specific lipids and proteins within or on LDs as key components that determine whether LD accumulation is linked to cellular and metabolic dysfunction is presented. We discuss emerging areas of LD biology and future research directions that are needed to advance our understanding of the role of LDs in NAFLD etiology.Major conclusionsImpairments in LD breakdown appear to contribute to disease progression, but inefficient incorporation of fatty acids (FAs) into LD-containing triacylglycerol (TAG) and the consequential changes in FA partitioning also affect NAFLD etiology. Increased LD abundance in hepatocytes does not necessarily equate to cellular dysfunction. While LD accumulation is the prerequisite step for most NAFLD cases, the protein and lipid composition of LDs are critical factors in determining the progression from simple steatosis. Further defining the detailed molecular mechanisms linking LDs to metabolic dysfunction is important for designing effective therapeutic approaches targeting NAFLD and its comorbidities.

Dataset Information

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD.

Background and aims

Methods

Results

Conclusions

Publications

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets