Review highlights role of retinol-binding protein-4 in non-alcoholic fatty liver disease

It is a known fact that drinking a large amount of alcohol even for a few days triggers fatty accumulation in the liver and ultimately leads to alcohol-related liver diseases. On the contrary, when fat accumulation occurs in the liver even in the absence of alcohol consumption, the condition is called non-alcoholic fatty liver disease (NAFLD). NAFLD is a potentially serious chronic liver disease that affects approximately 25% of adults worldwide. Patients with NAFLD are 33% more likely to suffer from coronary artery disease than healthy controls.

Although it is a serious and chronic liver disease closely linked to multiple other diseases, the underlying mechanisms associated with NAFLD remain more or less elusive. To this end, Chinese researchers recently conducted a meticulous study of the literature and composed a review based on their findings. Their article was published in Chinese medical journal July 06, 2022.

Dr. Chengfu Xu, corresponding author of the paper and senior researcher at Zhejiang University School of Medicine, China, observes: “In recent years, the prevalence of hepatocellular carcinoma associated with NAFLD has shown an increasing trend in many countries. The proportion of hepatocellular carcinomas attributed to NAFLD has tripled from 3.8% in 2001-2005 to 12 .2% in 2006-2010 in Korea. Similarly, this proportion increased from 2.6% in 1995-1999 to 19.5% in 2010-2014 in France. Consequently, NAFLD represents a significant burden on resources global health and the economy.

Retinol, or vitamin A, is a fat-soluble vitamin that is primarily stored in the liver and transported to other organs by binding to retinol-binding protein-4 (RBP4). In target organs (e.g. eyes), retinol can be taken up by binding of RBP4 to cell membrane receptors. However, the role of RBP4 in the development of insulin resistance and obesity has only recently received significant attention.

Although several observational studies have also demonstrated the association of serum RBP4 with the risks of NAFLD, the results showed several clear contradictions. Emerging clinical studies are focusing attention on the role of RBP4 in NAFLD. In the review article, the researchers presented a global overview of the RBP4 landscape and highlighted the most recent findings of clinical significance.

In the review, the authors cite several studies relevant to the problem under consideration. For example, they cite a 2005 publication in which researchers reported the association between elevated serum levels of RBP4 and insulin resistance. Dr. Xu and his colleague also cite conflicting research results. For example, although a Turkish study reported higher serum RBP4 levels in obese and NAFLD children, an Italian study found a negative correlation between serum RBP4 levels and NAFLD activity score in pediatric patients with NAFLD.

Dr. Xu explains, “These conflicting results may result from heterogeneity in methods for detecting fatty liver disease and race of study participants, as well as the limited study sample size. Studies not observing any significant association or inverse association between RBP4 level and NAFLD all diagnosed fatty liver by biopsy Liver biopsy is the gold standard for diagnosis of NAFLD It should be noted that none of these studies found found significant correlation between serum RBP4 level and body mass index, waist circumference, and fasting blood glucose or insulin levels, although the correlation has been confirmed in a large number of studies. “

The review also sheds light on some of the associated physiological mechanisms. For example, free RBP4 is known to be easily filtered in the kidneys due to its low molecular weight. However, transthyretin (TTR), a thyroid hormone transporter, binds to RBP4 and prevents it from being filtered out. A therapeutic agent called fenretinide, however, dissociates RBP4 from TTR, thereby facilitating renal excretion of RBP4, thereby lowering circulating levels of RBP4 in the process.

“First, clinical observations have shown that circulating levels of RBP4 are strongly associated with the risk of NAFLD, but discrepancies still exist. Second, fundamental studies have verified that RBP4 is involved in the pathogenesis of NAFLD by inducing lipogenesis liver de novo, by impairing fatty acid oxidation, exaggerating insulin resistance and promoting inflammation.Third, agents aimed at lowering circulating RBP4 levels and downregulating hepatic RBP4 expressions exerted protective effects against NAFLD. These findings raise the possibility of targeting RBP4 as a novel marker and potential therapeutic target for NAFLD.” concludes Dr. Xu.

Hopefully the scientific community will resolve existing conflicts by designing well-controlled experiments and large-scale clinical trials. In the meantime, kudos to the researchers for identifying the existing discrepancies and channeling the focus of research in the right direction.


Journal reference:

Huang, H & Xu, C., (2022) Retinol-4 binding protein and non-alcoholic fatty liver disease. Chinese medical journal.

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