RNA modification can protect against fatty liver

Schematic representation of m6A modifications (blue) that attach to RNA in the liver. Photo credit: Sallam Lab / UCLA

May also explain the liver fat differences between men and women.

A chemical modification that occurs in some

Ribonucleic acid (RNA) is a polymeric molecule similar to DNA that is essential in various biological roles in the coding, decoding, regulation and expression of genes. Both are nucleic acids, but unlike DNA, RNA is single-stranded. An RNA strand has a backbone made up of alternating sugar (ribose) and phosphate groups. One of four bases is bound to each sugar – adenine (A), uracil (U), cytosine (C) or guanine (G). Different types of RNA exist in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA) and transfer RNA (tRNA).

“> RNA Molecules as they are genetic instructions from

DNA, or deoxyribonucleic acid, is a molecule made up of two long strands of nucleotide that twist around each other to form a double helix. It is the genetic makeup of humans and almost all other organisms that carries genetic instructions for development, function, growth and reproduction. Almost every cell in a person’s body has the same DNA. Most of the DNA is in the nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA, or mtDNA).

“> DNA protein-making machinery of cells may provide protection against non-alcoholic fatty liver, a disease that results from the accumulation of fat in the liver and can lead to advanced liver disease, according to a new study by UCLA researchers.

The study conducted in mice also suggests that this modification – known as m6A, in which a methyl group attaches to an RNA chain – can occur in women at a different rate than men, which may explain why women tend to higher fat content in the liver. The researchers found that without the m6A modification, the differences in liver fat content between the sexes were drastically reduced.

Additionally, in a preclinical model, the researchers showed that gene therapy can be used to enhance key RNAs or add modifications to slow or reduce the severity of liver disease.


Fatty liver can develop when the amount of fat in the liver increases due to dietary or genetic factors, potentially leading to advanced liver scarring and disease, such as seen in cirrhosis and other conditions. High liver fat is also linked to an increased risk of cardiovascular disease.

In recent years, scientists have identified hundreds of chemical modifications, such as m6A, that can appear in RNA molecules that change the instructions that RNA makes to make proteins without affecting core DNA. Some modifications may be beneficial, as in the case of liver disease; others can be detrimental.


Using a unique mouse model that lacks m6A RNA modifications in the liver and a control model that contained the modifications, the authors compared the effects of diets with different fat content to assess the effects of the modifications on fatty liver. In addition, they used measurements from human patients who had undergone liver biopsy during bariatric surgery to correlate markers for m6A RNA modifications with liver fat content and inflammation.


A key question for the future is how genetic and environmental factors affect the body’s natural ability to produce RNA modifications. Since m6A appears to act as a protective control point that slows the accumulation of fat in the liver, the researchers hope their results will stimulate future research to develop therapies to improve chemical modifications to protect against liver disease and related diseases.

Reference: “Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits” until July 19, 2021, David A. Salisbury, David Casero, Zhengyi Zhang, Dan Wang, Jason Kim, Xiaohui Wu, Laurent Vergnes, Aashiq H. Mirza, Paola Leon- Mimila, Kevin J. Williams, Adriana Huertas-Vazquez, Samie R. Jaffrey, Karen Reue, Jianjun Chen and Tamer Sallam, July 19, 2021, Nature Metabolism.
DOI: 10.1038 / s42255-021-00427-2

The study was conducted by Dr. Tamer Sallam, an associate professor of medicine at the David Geffen School of Medicine at UCLA. Other authors included David Salisbury, Zhengyi Zhang, Dan Wang, Jason Kim, Xiaohui Wu, Laurent Vergnes, Kevin Williams, Adriana Huertas-Vazquez, and Karen Reue, all from UCLA; David Casero of Cedars-Sinai; Aashiq Mirza and Dr. Samie Jaffrey from Cornell University; Paola Leon-Mimila from the National Autonomous University of Mexico (UNAM); and Jianjun Chen from Hope City Medical Institute.

The study was published in the journal Nature Metabolism.

The study was funded by grants from the National Institutes of Health, a grant from the American Heart Association Transformational Project, and a Burroughs Wellcome Fund Career Award for Medical Scientists.

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