Hepatocyte RIPK1 Deficiency Sensitizes the Liver to Metabolic Challenges, Inducing Inflammation and Apoptosis

Core Concepts

Hepatocyte-specific deficiency of RIPK1 sensitizes the liver to metabolic challenges, such as short-term fasting or high-fat diet, leading to acute liver injury, hepatocyte apoptosis, inflammation, and compensatory proliferation.

Abstract

This study investigated the physiological role of RIPK1 in the liver and found that hepatocyte-specific RIPK1 deficiency (Ripk1Δhep mice) sensitized the liver to metabolic challenges, such as short-term fasting or high-fat diet feeding. Key findings: Short-term fasting induced significant liver injury, hepatocyte apoptosis, and inflammation in Ripk1Δhep mice, but not in control mice. Transcriptomic analysis revealed that fasting triggered an inflammatory response in Ripk1Δhep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing confirmed the increased recruitment of macrophages to the liver in Ripk1Δhep mice during fasting. Mechanistically, endoplasmic reticulum (ER) stress was involved in fasting-induced liver injury in Ripk1Δhep mice, and inhibition of ER stress rescued the liver phenotype. Similar effects were observed in Ripk1Δhep mice subjected to short-term high-fat diet feeding, suggesting that hepatocyte RIPK1 is essential for maintaining liver homeostasis during metabolic disturbances. Overall, this study reveals a critical role of RIPK1 in preserving liver homeostasis during metabolic challenges and provides insights into the interplay between cell death, inflammation, and liver adaptation to metabolic stress.

Stats

Serum alanine amino-transferase (ALT) levels were significantly increased in Ripk1Δhep mice compared to control mice after short-term fasting. Serum aspartate amino-transferase (AST) levels were significantly increased in Ripk1Δhep mice compared to control mice after short-term fasting. The number of TUNEL-positive cells (apoptotic cells) in the liver was significantly higher in Ripk1Δhep mice compared to control mice after short-term fasting. The number of cleaved caspase-3-positive cells (apoptotic cells) in the liver was significantly higher in Ripk1Δhep mice compared to control mice after short-term fasting.

Quotes

"Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice." "Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1Δhep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes." "Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1Δhep mice during fasting, highlighting the increased recruitment of macrophages to the liver."

Key Insights Distilled From

Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges

by Zhang,W., Zh... at www.biorxiv.org 03-07-2024

https://www.biorxiv.org/content/10.1101/2024.03.04.583302v1

Deeper Inquiries

How might the findings of this study be leveraged to develop personalized dietary or fasting regimens for individuals based on their RIPK1 gene expression or genetic variations?

The findings of this study provide valuable insights into the role of RIPK1 in maintaining liver homeostasis during metabolic challenges. Leveraging this knowledge, personalized dietary or fasting regimens could be developed for individuals based on their RIPK1 gene expression or genetic variations. For individuals with variations in the RIPK1 gene that make them more susceptible to liver injury or inflammation during fasting or high-fat dieting, personalized regimens could be tailored to minimize these risks. This could involve adjusting the duration or intensity of fasting periods, incorporating specific nutrients or supplements to support liver health, or implementing strategies to reduce inflammation and promote liver adaptation.

What other metabolic pathways or signaling cascades might be involved in the interplay between RIPK1, cell death, inflammation, and liver adaptation to metabolic challenges?

In addition to the pathways highlighted in the study, several other metabolic pathways and signaling cascades may be involved in the interplay between RIPK1, cell death, inflammation, and liver adaptation to metabolic challenges. These could include pathways related to oxidative stress, mitochondrial function, lipid metabolism, and glucose homeostasis. For example, oxidative stress pathways such as the Nrf2-Keap1 pathway may interact with RIPK1 to modulate cell survival and inflammation in response to metabolic stress. Similarly, mitochondrial dysfunction and alterations in lipid metabolism pathways could impact the susceptibility of liver cells to apoptosis and inflammation during metabolic challenges. Furthermore, signaling cascades involved in glucose sensing and insulin signaling may also play a role in the adaptive responses of the liver to fasting or high-fat dieting.

Could the insights gained from this study on the role of RIPK1 in liver homeostasis be extended to understand its potential involvement in the pathogenesis of other metabolic disorders, such as non-alcoholic fatty liver disease or diabetes?

The insights gained from this study on the role of RIPK1 in liver homeostasis could indeed be extended to understand its potential involvement in the pathogenesis of other metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD) or diabetes. Given the central role of RIPK1 in regulating cell death, inflammation, and metabolism, dysregulation of RIPK1 activity or expression could contribute to the development and progression of metabolic disorders. In the context of NAFLD, aberrant RIPK1 signaling may exacerbate liver injury, inflammation, and steatosis, leading to the progression of the disease. Similarly, in diabetes, dysregulation of RIPK1-mediated pathways could impact insulin sensitivity, glucose metabolism, and pancreatic function. Further research into the specific mechanisms by which RIPK1 influences these metabolic disorders could provide novel therapeutic targets for intervention and management.