Notes on Mechanisms of Liver Injury in Non-Alcoholic Steatohepatitis (NASH)

Abstract

• Non-Alcoholic Steatohepatitis (NASH): A disorder characterized by altered hepatic lipid homeostasis, liver injury through cell death, inflammation, and fibrosis.

• Research in NASH is evolving with integration from cell biology, microbiology, immunology, and genetics to enhance understanding of disease mechanisms.

Introduction

• NASH involves disruptions in lipid metabolism, cellular integrity, immune response, and tissue repair processes.

• The condition emerges from both intrahepatic events and external signals from the intestine and adipose tissue.

• Critical sections of study include:

  • Events leading to hepatic fat accumulation (hepatic steatosis)

  • Events causing liver injury, cell death, inflammation, and fibrosis

Mechanisms of Hepatic Steatosis

• Hepatic steatosis is essential for diagnosing NASH.

• Adipose Tissue Inflammation: In obesity, dysfunctional adipose tissue diverts triglycerides to the liver, influenced by cytokines like TNF and CCL2:

  • CCL2 attracts macrophages, intensifying inflammation.

  • TNF causes insulin resistance, leading to triglyceride lipolysis and excess fatty acids in circulation.

• Fatty Acid Sources: The liver's fatty acids arise from:

  1. Adipose tissue (77% in lean individuals, 60% in obese)

  2. Dietary fat (19% in lean, serving a lesser role in obese individuals)

  3. De novo lipogenesis (DNL), increasing from 4% to 26% in obesity.

• De Novo Lipogenesis (DNL):

  • Key regulated by SREBP-1.

  • SREBP-1 activity increases with insulin and ER stress, which can cause hepatic steatosis.

• Dietary Influences on DNL:

  • Simple sugars (especially fructose) significantly stimulate DNL.

  • High carbohydrate diets induce higher DNL; studies noted 30% reduction in hepatic lipids with low-carbohydrate diets.

Mechanisms of Liver Injury in NASH

A. Hepatocyte Death Mechanisms

• Lipotoxicity:

  • Saturated fatty acids (SFAs), particularly palmitate (C16:0) and stearate (C18:0), directly cause hepatocyte death via JNK activation.

  • ER stress and cell death via caspase-1 activation have been linked to lipid accumulation.

  • Excess cholesterol sensitizes hepatocytes to death by altering mitochondrial membrane function.

• Mitochondrial Dysfunction:

  • Increased fatty acid oxidation leads to oxidative stress and electron leakage, resulting in greater ROS production, impairing hepatocyte viability.

B. Hepatic Inflammation Mechanisms

• Inflammatory responses initiated by danger signals from damaged hepatocytes include:

  • Fatty acids and endotoxins that stimulate the innate immune response.

• Kupffer Cells:

  • The primary liver macrophage, triggers inflammation via TLR signaling and inflammasome activation.

  • Release of pro-inflammatory cytokines (TNF, IL-1β)that exacerbate steatosis and promote additional cytotoxicity.

C. Hepatic Fibrosis Mechanisms

• Hepatic Stellate Cell (HSC) Activation:

  • HSCs transition to a myofibroblastic phenotype during chronic injury.

  • The synergy of hepatocyte death, inflammation, and HSC activation foster liver fibrosis, with interplay of cytokines further regulating fibrogenesis.

Genetic and Environmental Factors Influencing NASH

• Hereditary Predisposition: Gene polymorphisms like PNPLA3 (I148M variant) are associated with increased hepatic steatosis and disease severity. Other relevant genes include NCAN, LYPAL1, GCKR, and PPP1R3B.

• Intestinal Microbiome: Gut bacteria contribute to energy extraction from food and fatty liver disease development. Dysbiosis, particularly increased Firmicutes, has been reported in various studies linking it to NASH.

• Interaction of Microbiome and Host Factors: Microbiome can promote conditions leading to metabolic endotoxemia, affecting liver health.

Conclusion

• NASH stems from obesity, dysfunctional adipose tissue, and is influenced by genetics and diet.

• New research highlights the importance of DNL, gut microbiome effects, and inflammasome activity in NASH pathogenesis, paving way for novel preventive and therapeutic strategies.