A decade ago, only a few people had heard of a condition called nonalcoholic fatty liver disease, also known as NAFLD, the most common form of liver disease which ranges from isolated steatosis to non-alcoholic steatohepatitis or NASH.

NAFLD is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol. However, the term also implies that too much fat is stored in their liver cells.

Fast forward to today and 1 in 3 people suffer from this chronic metabolic liver disease, including 1 in 10 children.* And yet, there are still no US Food and Drug Administration (FDA-) approved treatment for NAFLD.[1][2]

A recently meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). [3]

Today NAFLD is one of the leading causes of liver transplants and liver cancer, including in children. The disease is, however hard to diagnose because in most cases NAFLD does not cause symptoms and is frequently recognized as a result of diagnostic tests for other reasons that may point to a liver problem, including an unusual ultrasound or an abnormal liver enzyme test. [4]

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Navy dolphins
While there have been a decade of hypotheses as to how NAFLD emerged this rapidly, an unlikely population of Navy dolphins may help find the answer. NAFLD may be related to – nutritional deficiencies of an essential nutrient called C15:0, also known as pentadecanoic acid, an odd-chain saturated fat found in butter that, an essential fatty acid that is necessary in the diet to support long-term metabolic and heart health.

While working to support the long-term health of Navy dolphins for over a decade,  Stephanie Venn-Watson, DVM, MPH. a veterinary epidemiologist and public health scientist, noticed that there “were increasing cases of dolphins with elevated liver enzymes, detected during their routine health exams. When we looked at archived liver tissue samples under the microscope, we surprisingly found that more than 1 out of 3 bottlenose dolphins (Tursiops truncatus) had fatty liver disease.” [5]

After publishing these findings in 2013, Venn-Watson, now co-founder and Chief Executive Officer of Seraphina Therapeutics, was contacted by Jeffrey Schwimmer, MD, a gastroenterologist at Rady Children’s Hospital in San Diego, CA, and the world’s leader in the understanding and management of pediatric NAFLD. What followed was a collaboration in which Venn-Watson and Schwimmer have been working in parallel to understand the mechanisms of NAFLD in dolphins and humans, with hopes of finding a cure.

Venn-Watson discovered that the healthiest dolphins had higher levels of C15:0 compared those who had chronic metabolic conditions, including fatty liver disease, suggesting that C15:0 may be a key nutrient needed to protect dolphins’ liver health. [6] This surprising discovery of C15:0’s importance was recently highlighted in a New York Times Science feature article and is a TEDx talk.

To test her hypothesis that C15:0 is a liver-protective nutrient Venn-Watson and her team conducted eight studies over three years.  The outcomes of these studies demonstrated that C15:0 is a beneficial fatty acid that could slow the advancement of NAFLD. These outcomes also showed that daily oral treatment with C15:0 stopped severe liver fibrosis in NAFLD models [7], is a dose-dependent anti-inflammatory and antifibrotic activities [7] in human cells systems mimicking components of NAFLD, and has liver-protective benefits, by protecting cell membranes against damage, and as an anti-inflammatory and antifibrotic PPAR-ɑ/δ agonist. [8]

Concurrently, Schwimmer and his team completed an independent and extensive study including 237 children, which showed that patients with higher C15:0 blood levels had less fat in their liver. [9] In addition to Schwimmer research, scientists at MD Anderson Cancer Center have shown that higher C15:0 is linked to a lower risk of severe NAFLD. [10][11]

Intake of milk and butter
While humans’ primary dietary source of C15:0 is whole fat cow’s milk and butter, intake of these foods has declined precipitously over the past 40 years as consumers have opted for plant-based milks, which contain no C15:0. As a result, population wide C15:0 levels have been declining. [12]

However, the amount of C15:0 in whole fat cow’s milk is dependent on what cows are fed, and even types of grasses fed to cows can have a meaningfully impact on the levels of C15:0 in their milk. [13] The risk of nutritional C15:0 deficiencies has increased further among aging populations, since C15:0 levels naturally decline with age, in both humans and dolphins. [14]

Based on the outcomes of the studies, Venn-Watson and Edward A. Dennis, Ph.D., a leader in the study of fatty acids and bioactive lipids at Department of Chemistry and Biochemistry and Department of Pharmacology, University of California at San Diego, La Jolla, CA, laid out evidence supporting C15:0 as an essential fatty acid, making C15:0 the first essential fatty acid to be discovered since omega-3, over 90 years ago.

“The timing of populationwide C15:0 nutritional declines coupled with the alarming rise in NAFLD do not appear to be coincidental,” Venn-Watson said.

“The good news is that these nutritional deficiencies can be fixed,” she concluded.

Ongoing research
To evaluate C15:0’s potential physiological benefits for young adults with a history of NAFLD. Schwimmer and his team at the University of California, San Diego, CA, are conducting a clinical trial. The study, funded in part by the Office of Naval Research is designed to further evaluate the health benefits of C15:0 for dolphins with NAFLD.

“We have the Navy’s dolphins to thank for the discovery of C15:0 as an essential fatty acid and a potential means to stem the global rise in NAFLD,” Venn-Watson said. “It feels even better knowing that this discovery may help children, too.”

Note: * The overall, worldwide prevalence of nonalcoholic fatty liver disease or NAFLD was estimated to be 32.4% (95% CI 29.9–34.9). However, over time, the prevalence of the disease increased significantly, from 25.5% (20.1–31.0) before 2005 to 37.8% (32.4–43.3) after 2016 (p=0.013). In addition, the incidence of NAFLD is significantly higher in men than in women (39.7% [36.6–42.8] vs 25.6% [22.3–28.8]; p<0.0001). [1]

Clinical trials
C15:0 Supplementation in Young Adults at Risk for Metabolic Syndrome – NCT04947176

Reference
[1] Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, Swain MG, Congly SE, Kaplan GG, Shaheen AA. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022 Sep;7(9):851-861. doi: 10.1016/S2468-1253(22)00165-0. Epub 2022 Jul 5. PMID: 35798021.
[2] Yoo W, Gjuka D, Stevenson HL, Song X, Shen H, Yoo SY, Wang J, Fallon M, Ioannou GN, Harrison SA, Beretta L. Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid. PLoS One. 2017 Dec 15;12(12):e0189965. doi: 10.1371/journal.pone.0189965. PMID: 29244873; PMCID: PMC5731750.
[3] Mantovani A, Petracca G, Beatrice G, Csermely A, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut. 2022 Apr;71(4):778-788. doi: 10.1136/gutjnl-2021-324191. Epub 2021 Mar 8. PMID: 33685968.
[4] Pais R, Barritt AS 4th, Calmus Y, Scatton O, Runge T, Lebray P, Poynard T, Ratziu V, Conti F. NAFLD and liver transplantation: Current burden and expected challenges. J Hepatol. 2016 Dec;65(6):1245-1257. doi: 10.1016/j.jhep.2016.07.033. Epub 2016 Jul 30. PMID: 27486010; PMCID: PMC5326676.
[5] Venn-Watson S, Benham C, Carlin K, DeRienzo D, St. Leger J “Hemochromatosis and Fatty Liver Disease: Building Evidence for Insulin Resistance in Bottlenose Dolphins (Tursiops Truncatus). Journal of Zoo and Wildlife Medicine, 43(3s); 2 September 2012 [Article]
[6] Venn-Watson S, Baird M, Novick B, Parry C, Jensen ED. Modified fish diet shifted serum metabolome and alleviated chronic anemia in bottlenose dolphins (Tursiops truncatus): Potential role of odd-chain saturated fatty acids. PLoS One. 2020 Apr 7;15(4):e0230769. doi: 10.1371/journal.pone.0230769. PMID: 32259832; PMCID: PMC7138614.
[7] Venn-Watson S, Lumpkin R, Dennis EA. Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep. 2020 May 18;10(1):8161. doi: 10.1038/s41598-020-64960-y. PMID: 32424181; PMCID: PMC7235264.
[8] Venn-Watson SK, Butterworth CN. Broader and safer clinically-relevant activities of pentadecanoic acid compared to omega-3: Evaluation of an emerging essential fatty acid across twelve primary human cell-based disease systems. PLoS One. 2022 May 26;17(5):e0268778. doi: 10.1371/journal.pone.0268778. PMID: 35617322; PMCID: PMC9135213.
[9] Sawh MC, Wallace M, Shapiro E, Goyal NP, Newton KP, Yu EL, Bross C, Durelle J, Knott C, Gangoiti JA, Barshop BA, Gengatharan JM, Meurs N, Schlein A, Middleton MS, Sirlin CB, Metallo CM, Schwimmer JB. Dairy Fat Intake, Plasma Pentadecanoic Acid, and Plasma Iso-heptadecanoic Acid Are Inversely Associated With Liver Fat in Children. J Pediatr Gastroenterol Nutr. 2021 Apr 1;72(4):e90-e96. doi: 10.1097/MPG.0000000000003040. PMID: 33399331; PMCID: PMC8842839.
[10] Yoo W, Gjuka D, Stevenson HL, Song X, Shen H, Yoo SY, Wang J, Fallon M, Ioannou GN, Harrison SA, Beretta L. Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid. PLoS One. 2017 Dec 15;12(12):e0189965. doi: 10.1371/journal.pone.0189965. PMID: 29244873; PMCID: PMC5731750.
[11] Jiao J, Kwan SY, Sabotta CM, Tanaka H, Veillon L, Warmoes MO, Lorenzi PL, Wang Y, Wei P, Hawk ET, Almeda JL, McCormick JB, Fisher-Hoch SP, Beretta L. Circulating Fatty Acids Associated with Advanced Liver Fibrosis and Hepatocellular Carcinoma in South Texas Hispanics. Cancer Epidemiol Biomarkers Prev. 2021 Sep;30(9):1643-1651. doi: 10.1158/1055-9965.EPI-21-0183. Epub 2021 Jun 21. PMID: 34155064; PMCID: PMC8419070.
[12] Zheng JS, Imamura F, Sharp SJ, Koulman A, Griffin JL, Mulligan AA, Luben R, Khaw KT, Wareham NJ, Forouhi NG. Changes in plasma phospholipid fatty acid profiles over 13 years and correlates of change: European Prospective Investigation into Cancer and Nutrition-Norfolk Study. Am J Clin Nutr. 2019 Jun 1;109(6):1527-1534. doi: 10.1093/ajcn/nqz030. PMID: 30997506; PMCID: PMC6537938.
[13] van Gastelen S, Antunes-Fernandes EC, Hettinga KA, Klop G, Alferink SJ, Hendriks WH, Dijkstra J. Enteric methane production, rumen volatile fatty acid concentrations, and milk fatty acid composition in lactating Holstein-Friesian cows fed grass silage- or corn silage-based diets. J Dairy Sci. 2015 Mar;98(3):1915-27. doi: 10.3168/jds.2014-8552. Epub 2015 Jan 9. PMID: 25582590.
[14] Tsoukalas D, Alegakis AK, Fragkiadaki P, Papakonstantinou E, Tsilimidos G, Geraci F, Sarandi E, Nikitovic D, Spandidos DA, Tsatsakis A. Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults. Int J Mol Med. 2019 Jan;43(1):233-242. doi: 10.3892/ijmm.2018.3989. Epub 2018 Nov 14. PMID: 30431095; PMCID: PMC6257830.

Featured image by Ranae Smith on Unsplash Used with permission.

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