What is the role of insulin resistance in fatty liver disease?

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What is the role of insulin resistance in fatty liver disease?

The Role of Insulin Resistance in Fatty Liver Disease

Insulin resistance is a critical factor in the development and progression of non-alcoholic fatty liver disease (NAFLD). It contributes to hepatic steatosis, inflammation, and fibrosis through multiple pathways. Here’s a detailed look at how insulin resistance plays a role in fatty liver disease:

1. Mechanism of Insulin Resistance in Fatty Liver Disease

Increased Lipolysis and Free Fatty Acid (FFA) Release:

Insulin resistance in adipose tissue leads to increased lipolysis, resulting in elevated levels of FFAs in the bloodstream. These FFAs are transported to the liver, where they are taken up and stored as triglycerides, contributing to hepatic steatosis (fat accumulation in the liver) (AJMC) (Health.mil).

Sources:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NAFLD and Insulin Resistance
American Diabetes Association Insulin Resistance

2. De Novo Lipogenesis (DNL)

Stimulation of Fat Synthesis:

Insulin resistance promotes de novo lipogenesis, the process by which excess carbohydrates are converted into fatty acids in the liver. This process is driven by hyperinsulinemia (excess insulin) and hyperglycemia (high blood sugar levels), leading to increased fat synthesis and storage in the liver (AJMC) (Health.mil).

Key Enzymes:

Enzymes such as sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP) are upregulated in insulin resistance, enhancing the liver’s capacity to synthesize fatty acids from carbohydrates (AJMC).

Sources:

Journal of Hepatology Role of Insulin Resistance in NAFLD
Cleveland Clinic Metabolic Syndrome and NAFLD

3. Impaired Fatty Acid Oxidation

Reduction in Fat Utilization:

Insulin resistance impairs the ability of hepatocytes (liver cells) to oxidize fatty acids, leading to their accumulation. Normally, insulin regulates fatty acid oxidation by modulating enzymes involved in this process. In insulin resistance, this regulation is disrupted, reducing the breakdown of fatty acids in the liver (AJMC) (Health.mil).

Sources:

Mayo Clinic Fatty Liver Disease and Insulin Resistance
American Association for the Study of Liver Diseases (AASLD) NAFLD Guidelines

4. Inflammation and Oxidative Stress

Inflammatory Cytokines:

Insulin resistance is associated with chronic low-grade inflammation. Adipose tissue in obese individuals releases pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which can promote liver inflammation and progression to non-alcoholic steatohepatitis (NASH) (AJMC) (Health.mil).

Oxidative Stress:

Increased FFA influx and impaired fatty acid oxidation lead to the production of reactive oxygen species (ROS) in the liver. This oxidative stress damages hepatocytes, contributing to liver inflammation, fibrosis, and ultimately cirrhosis (AJMC).

Sources:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) NAFLD and NASH
Hepatology Journal Oxidative Stress in NAFLD

Conclusion

Insulin resistance plays a multifaceted role in the development and progression of fatty liver disease through mechanisms such as increased lipolysis, enhanced de novo lipogenesis, impaired fatty acid oxidation, and inflammation. Addressing insulin resistance through lifestyle changes, medications, and management of associated conditions like obesity and diabetes is crucial for preventing and treating NAFLD.