Moreover, diabetes and obesity are common metabolic disorders associated with liver disease, primarily non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease, in turn, can further cause cirrhosis and liver cancer. The non-alcoholic fatty liver disease involves a spectrum of disorders ranging from isolated hepatic steatosis (accumulation of fat in the liver), to non-alcoholic steatohepatitis (inflammation of the liver, as well as fat accumulation) and fibrosis (formation of excess fibrous tissue).
The prevalence of non-alcoholic fatty liver disease parallels the prevalence of obesity and type 2 diabetes mellitus.1,4
Obesity and Non-Alcoholic Liver Disease
What is Obesity?
Obesity is a condition involving a high body mass index (BMI), primarily greater than 30 kg/m2. Experienced by populations of all ages across the globe, it is associated with a range of health conditions, such as:
- Insulin resistance or type 2 diabetes
- Non-alcoholic fatty liver disease
- Cardiovascular problems
- Degenerative disorders
- Pulmonary problems
- Certain cancers
Abdominal obesity, coupled with insulin resistance, dyslipidemia (high levels of ‘bad’ cholesterol) and hypertension (high blood pressure), is altogether known as metabolic syndrome. Obesity and metabolic syndrome are caused as a result of factors, such as a sedentary lifestyle, overnutrition, genetics (Prader-Willi Syndrome), lack of exercise, underlying medical conditions (Cushing’s syndrome, hypothyroidism), certain medications (corticosteroids, antidepressants, epilepsy medications), and subsequent weight gain. All of this is associated with chronic inflammation 3,6.
How does obesity influence liver disease?
Obesity and non-alcoholic fatty liver disease are closely associated. Excess fat, as seen in obesity, can induce insulin resistance and inflammatory immune-mediated signals. Obesity is marked by the increase in IHTG – intrahepatic triglyceride content. IHTG is a marker of insulin resistance, alterations in glucose metabolism, fatty acid metabolism, lipoprotein metabolism, and inflammation, which can induce a disturbance in fluid balance within the body. Moreover, hepatic steatosis, or excess fat around your liver, can arise due to increased uptake and synthesis of fatty acid and fatty acid oxidation.
What is the biological basis of the association between obesity and non-alcoholic fatty liver disease?
The adipose tissue within the body is responsible for a range of functions, including the secretion of adipokine proteins that influence the liver.
Examples include TNF-α (tumour necrosis factor-alpha) inducing programmed cell death to prevent mutations and inflammation. Adiponectin is another adipokine that promotes anti-inflammatory effects, and levels are reduced during obesity and type 2 diabetes mellitus.
Excess adipose tissue seen in obesity leads to higher levels of inflammation and cell death, thereby promoting liver damage. Since the body fat storages expand during excessive calorie intake, lipid metabolism alters and adipose tissue inflammation occurs.
These sites of fat deposition can potentially lead to insulin resistance and receptor cell abnormalities in the insulin signalling pathways. This leads to a general homoeostatic imbalance, and subsequent damage and inflammation. Primary non-alcoholic liver disease results from this mechanism and can progress to liver cirrhosis, hypertension, hepatocellular cancer, and liver failure.1,2,5,7,12
Diabetes and Non-Alcoholic Liver Disease
What is Type 2 Diabetes Mellitus?
Diabetes mellitus refers to a condition marked by excess glucose in the blood due to improper, or a complete lack of, pancreatic function. The body digests dietary material to produce glucose – however, due to impaired pancreatic functioning, the body develops insulin resistance. Insulin, produced by the pancreas, is vital in glucose regulation within the body. Insulin resistance caused by improper pancreatic functioning leads to a pooling of excess glucose in the blood and a reduced level in the cells. Type 2 diabetes mellitus can develop at any age group, but primarily affects middle-aged or older individuals. If left unmanaged, diabetes can progress into heart disease, strokes, nerve damage, kidney disease, foot problems, eye disease, sexual health problems, urogenital conditions, and more. It is also linked to sleep apnoea, dementia, degenerative disorders, and mental health issues.1,6
How does Type 2 diabetes mellitus influence liver disease?
Liver cirrhosis, brought about by liver disease, is associated with insulin resistance. As explained above, insulin resistance is a primary feature of Type 2 diabetes. However, type 2 diabetes mellitus is not a causative factor of non-alcoholic liver disease, but is a contributor (risk factor). In type 2 diabetes, excess fat can accumulate in the liver, and nearby organs and tissues. This can increase the risk of developing non-alcoholic steatohepatitis, where liver fat can potentially induce inflammatory, immune-mediated responses. This, in turn, can lead to the formation of scar tissue in the affected areas, causing liver cirrhosis. Accumulation of scar tissue can potentially render the organ impaired.1
Glucose levels are primarily elevated in type 2 diabetes. This increases the synthesis of triglycerides and fatty acid components. Additionally, the body reduces the production of very low density lipoprotein (VLDL). This contributes to insulin resistance and fat accumulation in the liver, which can further lead to the activation of kinases (enzymes) in the serum of insulin sensitive cells. These include Jun N-terminal kinase (JNK), inhibitor of nuclear factor κB (NF-κB) kinase (IKK), and novel isoforms of protein kinase C (PKC). These enzymes can alone, or in combination, affect insulin via a cascade of signals whilst simultaneously causing inflammation by forming compounds (AP-1 and NF-κB). They activate a variety of genes that support inflammatory responses, cytokines, chemokines, and other molecules that allow cell adhesion. This results in progressive systemic inflammation, which further leads to cirrhosis and damage, amongst other impairments of regulatory actions.
Insulin resistance therefore is associated with liver disease, obesity and type 2 diabetes.1,4,5,8,9,10,11,13,14,15,16
- Al-Goblan, A. S., Al-Alfi, M. A., & Khan, M. Z. (2014). Mechanism linking diabetes mellitus and obesity. Diabetes, metabolic syndrome and obesity : targets and therapy, 7, 587–591. https://doi.org/10.2147/DMSO.S67400
- Birkenfeld, A. L., & Shulman, G. I. (2014). Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology (Baltimore, Md.), 59(2), 713–723. https://doi.org/10.1002/hep.26672
- Crinò, A., Fintini, D., Bocchini, S., & Grugni, G. (2018). Obesity management in Prader–Willi syndrome: current perspectives. Diabetes, metabolic syndrome and obesity: targets and therapy, 11, 579.
- Czaja M. J. (2010). JNK regulation of hepatic manifestations of the metabolic syndrome. Trends in endocrinology and metabolism: TEM, 21(12), 707–713. https://doi.org/10.1016/j.tem.2010.08.010
- Daniel, P. V., Dogra, S., Rawat, P., Choubey, A., Khan, A. S., Rajak, S., Kamthan, M., & Mondal, P. (2021). NF-κB p65 regulates hepatic lipogenesis by promoting nuclear entry of ChREBP in response to a high carbohydrate diet. The Journal of biological chemistry, 296, 100714. https://doi.org/10.1016/j.jbc.2021.100714
- Finsterer, J., & Stöllberger, C. (2016). Neurological complications of cardiac disease (heart brain disorders). Minerva medica, 107(1), 14–25.
- Heyens, L., Busschots, D., Koek, G., Robaeys, G., & Francque, S. (2021). Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment. Frontiers In Medicine, 8. https://doi.org/10.3389/fmed.2021.615978
- Kawano, Y., & Cohen, D. E. (2013). Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. Journal of gastroenterology, 48(4), 434–441. https://doi.org/10.1007/s00535-013-0758-5
- Lefere, S., Van de Velde, F., Devisscher, L., Bekaert, M., Raevens, S., Verhelst, X., Van Nieuwenhove, Y., Praet, M., Hoorens, A., Van Steenkiste, C., Van Vlierberghe, H., Lapauw, B., & Geerts, A. (2017). Serum vascular cell adhesion molecule-1 predicts significant liver fibrosis in non-alcoholic fatty liver disease. International journal of obesity (2005), 41(8), 1207–1213. https://doi.org/10.1038/ijo.2017.102
- Luedde, T., & Schwabe, R. F. (2011). NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nature reviews. Gastroenterology & hepatology, 8(2), 108–118. https://doi.org/10.1038/nrgastro.2010.213
- Pais, R., Pascale, A., Fedchuck, L., Charlotte, F., Poynard, T., & Ratziu, V. (2011). Progression from isolated steatosis to steatohepatitis and fibrosis in nonalcoholic fatty liver disease. Clinics and research in hepatology and gastroenterology, 35(1), 23–28. https://doi.org/10.1016/j.gcb.2010.06.004
- Paredes-Turrubiarte, G., González-Chávez, A., Pérez-Tamayo, R., Salazar-Vázquez, B. Y., Hernández, V. S., Garibay-Nieto, N., Fragoso, J. M., & Escobedo, G. (2016). Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients. Clinical and experimental medicine, 16(2), 193–202. https://doi.org/10.1007/s10238-015-0347-4
- Perla, F. M., Prelati, M., Lavorato, M., Visicchio, D., & Anania, C. (2017). The Role of Lipid and Lipoprotein Metabolism in Non-Alcoholic Fatty Liver Disease. Children (Basel, Switzerland), 4(6), 46. https://doi.org/10.3390/children4060046
- Sarwar, R., Pierce, N., & Koppe, S. (2018). Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes, metabolic syndrome and obesity : targets and therapy, 11, 533–542. https://doi.org/10.2147/DMSO.S146339
- Tilg H. (2010). The role of cytokines in non-alcoholic fatty liver disease. Digestive diseases (Basel, Switzerland), 28(1), 179–185. https://doi.org/10.1159/000282083
- Zhang, H., Ma, Z., Pan, L. et al. Hepatic fat content is a determinant of metabolic phenotypes and increased carotid intima-media thickness in obese adults. Sci Rep 6, 21894 (2016). https://doi.org/10.1038/srep21894