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. 2023 Nov 20;71(48):18674–18684. doi: 10.1021/acs.jafc.3c06300

Branched-Long-Chain Monomethyl Fatty Acids: Are They Hidden Gems?

Siqing Mao †, Ziling Liu †, Yuan Tian †, Dan Li †, Xin Gao †, Yanqiong Wen †, Tao Peng †, Weijun Shen ‡, Dingfu Xiao ‡, Fachun Wan ‡,*, Lei Liu †,*
PMCID: PMC10705331  PMID: 37982580

Abstract

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Branched-long-chain monomethyl fatty acids (BLCFA) are consumed daily in significant amounts by humans in all stages of life. BLCFA are absorbed and metabolized in human intestinal epithelial cells and are not only oxidized for energy. Thus far, BLCFA have been revealed to possess versatile beneficial bioactivities, including cytotoxicity to cancer cells, anti-inflammation, lipid-lowering, reducing the risk of metabolic disorders, maintaining normal β cell function and insulin sensitivity, regulation of development, and mitigating cerebral ischemia/reperfusion injury. However, compared to other well-studied dietary fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), BLCFA has received disproportionate attention despite their potential importance. Here we outlined the major food sources, estimated intake, absorption, and metabolism in human cells, and bioactive properties of BLCFA with a focus on the bioactive mechanisms to advocate for an increased commitment to BLCFA investigations. Humans were estimated to absorb 6–5000 mg of dietary BLCFA daily from fetus to adult. Notably, iso-15:0 inhibited the growth of prostate cancer, liver cancer and T-cell non-Hodgkin lymphomas in rodent models at the effective doses of 35–105 mg/kg/day, 70 mg/kg/day, and 70 mg/kg/day, respectively. Feeding formula prepared with 20% w/w BLCFA mixture to neonatal rats with enterocolitis mitigated the intestine inflammation. Iso-15:0 at doses of 10, 40, and 80 mg/kg relieved brain ischemia/reperfusion injury in rats. In the future, it is crucial to conduct research to establish the epidemiology of BLCFA intake and their impacts on health outcomes in humans as well as to fully uncover the underlying mechanisms for their bioactivities.

Keywords: branched-chain fatty acids, dietary fats, biological activity, mechanism

1. Introduction

Branched-long-chain monomethyl fatty acids (BLCFA) represent a class of saturated long-chain fatty acids with one methyl branch. BLCFA can be obtained from many common foods, such as ruminant products (milk, cheese, and meat), fish, chia seeds, fermented foods, and others. Based on dietary patterns, the daily intake of BLCFA by humans can be estimated. Also, BLCFA are normal constituents of human tissues/cells because they exist in vernix caseosa,1 sebaceous gland,2,3 skin,4 and blood.5 BLCFA will be bioactive rather than inert once they are absorbed by humans. There is growing evidence that these dietary fatty acids (FA) are functional in antiproliferation of cancer cells, anti-inflammation, lipid-lowering, reducing the risk of metabolic disorders, maintaining normal β cell function and insulin sensitivity, regulation of development, and mitigating cerebral ischemia/reperfusion injury. However, the bioactivity and underlying mechanism of dietary BLCFA have long been neglected compared with other well-known dietary FA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There have been several recent excellent reviews describing BLCFA synthesis, potential health benefits and anticancer mechanisms.6−10 In this review, we profiled the estimated daily intake by humans at all stages of life, represented the absorption and metabolism in human cells, and provided the updated functions and the underlying functional mechanisms of BLCFA, aiming to expand our understanding of the role of these common but overlooked dietary FA in biology.

2. Search Strategy

This review was prepared based on PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Web of Science (https://www.webofscience.com/wos) databases. We searched articles published in English before June 26, 2023. The search terms included “odd- and branched-chain fatty acids” OR “branched-chain fatty acids” OR “branched fatty acids” OR “BCFA” OR “monomethyl branched-chain fatty acid” OR “mmBCFA” OR “methylhexadecanoic acid” OR “methyl tetradecanoic acid” OR “methyltetradecanoic acid” OR “13-methyltetradecanoic acid” OR “13-MTD”. The initial search generated 4856 articles, and 3180 articles remained after removing duplicates. By reviewing the title, abstract, and reading the full text, we determined whether the article was suitable for inclusion. In addition, other references were obtained by hand-searching the list of references. Finally, 95 publications were determined (Figure 1).

Figure 1.

Figure 1

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Search strategy.

The included literature was generally divided into the following categories: common food sources of BLCFA, estimated intake of BLCFA, bioactivity of BLCFA, and the mechanism of BLCFA function.

3. Structures of BLCFA

Branched-chain fatty acids (BCFA) are a type of fatty acid with one or more branched chains on the linear carbon skeleton, and the branched chains are mostly methyl. According to the length of the main carbon chain, BCFA can be divided into short-chain branched fatty acids (carbon atoms less than 6), medium-chain branched fatty acids (carbon atoms 6–12), long-chain branched fatty acids (carbon atoms 13–21), and very long-chain branched fatty acids (carbon atoms more than 21). Among them, BLCFA is the most abundant BCFA detected in common foods. BCFA can be further divided into iso-branched-chain fatty acids (iso-BCFA) and anteiso-branched-chain fatty acids (anteiso-BCFA) based on the position of the methyl-branched chain. Iso-BCFA represent the methyl group on the penultimate carbon atom, and anteiso-BCFA represent the methyl group on the antepenultimate carbon atom (Figure 2).

Figure 2.

Figure 2

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Structure of C17:0, iso-17:0 and anteiso-17:0.

4. Food Sources of BLCFA

4.1. Animal Sources

Table 1 lists the food sources of BLCFA and their levels. Ruminant products, like milk, beef, and cheese, are a major animal-related source for BLCFA. The main BLCFA therein are these with 13– 18 carbon atoms.11−13 Most of them are synthesized by rumen bacteria,14 which is subject to the regulation of the composition of the diet.15 In cow milk, the total BLCFA levels range from 1.37% to 3.44% (w/w of total FA), mainly including iso-15:0, anteiso-15:0, iso-16:0, iso-17:0, and anteiso-17:0.10,16−18 Yak milk contains more BLCFA. This is because 100 g of yak milk provides 274 mg of BLCFA,19 which is higher than 45.5–64.9 mg/100 g in milk.20−22 In beef, BLCFA are about 1.60–1.89% of the total FA, and iso-17:0, anteiso-17:0 are the major ones.20 Total BLCFA content in cheeses is 1.41–2.94%,20,23,24 and anteiso-15:0 and anteiso-17:0 are the most.25 In addition, the content of BLCFA in cow milk is also affected by the lactation period and breed.26

Table 1. Content of BLCFA in Foods.

food percentage of total fatty acids (%) levels in foods
Animal Sources
yak milk 2.19–617−19,42a 27419b
cow milk 1.37–3.4410,16−18a 45.5–64.920−22b
sheep milk 2.2941a 204–50210c
goat milk 1.12–2.3017,18,42a 109–18010c
camel milk 2.16–6.0416−18,42a  
cheese 1.41–2.9420,23,24a 75–833.320,21b
butter 1.8420a 1470.320b
yogurt 1.75–2.0120a 61.520b
beef 1.60–1.8920a 315–36020,21b
tuna 0.1420a 7.720b
Indian marine fish 2.86–7.7931a  
American wild freshwater fish 0.52–2.1730a 3.6–34.630b
fish oil 1.6–7.6932−34a  
Plant Sources
chia seeds 0.3137a 32.237c
ginkgo biloba 1.837a 25.137c
pine nut 0.0337a 6.037c
brussels sprouts 3.737a 5.937c
Human Milk
  0.36–0.7616,41,42a 4.27–7.945d
Fermented Foods
natto 147a 21–14347b
douchi 0.0847a 6–847b
kimchi 0.6447a 347b
miso 0.3747a 23–2447b
shrimp paste 1.6347a 6–3947b
fish sauce liquid 0.6247a 147b
fish sauce (paste-like) 0.7347a 29–3147b
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a

g/100 g of total fatty acids.

b

mg/100 g food.

c

mg/serving.

d

mg/100 mL.

Aquatic animals also contain BLCFA, such as holothurian, freshwater, and marine fish. In sea cucumber, anteiso-15:0 is the most abundant BLCFA,27 accounting for 4–17.7% of the total FA.28,29 The content of BLCFA generally follows the pattern of higher in winter or spring and lower in summer.29 This follows the same trend of the dynamics of bacteria, which are the main sources of BLCFA in holothurian. In wild freshwater fish, the muscular BLCFA levels are 0.52–2.17% of total FA,30 which is lower than that of marine fish (2.86–7.79% of total FA).31 Fish oil, a common dietary supplement, can provide a variety of BLCFA. The total BLCFA is about 1.6–7.69% of total FA in saltwater fish oil.32,33 The total BLCFA in freshwater fish oil is 1.61–4.06% of total FA.34

4.2. Plant Sources

BLCFA is also found in a few edible plants, including Brussels sprouts, chia seeds, ginkgo fruits, and pine nuts. BLCFA exist in the lipids/wax layer of Brussels sprouts.35,36 Their main BLCFA include anteiso-17:0 and anteiso-19:0. Anteiso-17:0 is the most one, accounting for 2.6% of total FA.36 The top three BLCFA in chia seed are anteiso-17:0, anteiso-19:0, and anteiso-21:0, and total BLCFA level is approximately 0.31% of total FA.37 Other seed foods also have a small amount of BLCFA. Anteiso-17:0 was the only BLCFA detected in ginkgo nuts and pinaceae seed oils, accounting for 0.86% and 0.02–1.15% of total FA, respectively.38,39

4.3. Human Breast Milk

Human breast milk is the predominant source of BLCFA for infants.40 The level of BLCFA in human breast milk is about 0.36–0.76% of total FA.16,41,42 By contrast, the mean concentration of DHA level in breast milk is 0.32% of total FA.43 The composition of BLCFA is affected by pregnancy duration and lactation. BLCFA levels are higher in term breast milk compared with preterm breast milk.44 They are at a high level in colostrum and low in mature milk.44 Moreover, the level of total BLCFA varies from region to region because of the different dietary patterns in the different regions. A recent study indicated that Cincinnati was the highest, followed by Mexico and Shanghai (7.90 ± 0.41, 6.10 ± 0.36, and 4.27 ± 0.25 mg/100 mL, respectively).45 Interestingly, the concentrations of iso-14:0, anteiso-15:0, and iso-16:0 are influenced by the maternal intake of dairy products, while the iso-16:0 level is influenced by the maternal intake of beef.45

4.4. Fermented Foods

Natto, shrimp paste, and Douchi are daily fermented foods in Asian countries. Microorganisms play a vital role in the fermentation of these foods. For example, Bacillus subtilis, which is used in natto production, possesses about 95% of total FA as BLCFA in the cell membrane.46 The composition of BLCFA in natto is similar to that of this bacterium. Iso-17:0 increased significantly after dried shrimp paste fermentation, accounting for 0.5% of total FA.47 Douchi also provides multiple BLCFA at a low concentration (0.08%).47

5. Estimated Intake of BLCFA by Humans

Because of the universal distribution in foods, BLCFA are ingested in all life stages of humans, from fetuses to adults. BLCFA intake even exceeds those of many other bioactive FA. A fetus ingests BLCFA by swallowing vernix caseosa suspended in amniotic fluid.48 About 90% of them disappear in the intestine, and only 10% are excreted in feces, indicating BLCFA are incorporated and utilized by the fetus.48 The estimated intake of BLCFA in a fetus is about 6 mg per day in the last month of pregnancy.49 Infants approximately absorb 19 mg BLCFA per 100 mL of milk.49 Taking 1-month-old male infants (4.5 kg) and 3-month-old male infants (6.5 kg) as examples, they roughly intake BLCFA 25 and 23 mg per kg body weight per day, respectively. This is higher than the intake of DHA (13 mg and 12 mg per kg body weight per day, respectively).49

American children aged 2–11 years consume about 323–423 mg of BLCFA per day.20,49 By contrast, children aged 4–7 years are estimated to take in DHA and arachidonic acid (ARA) at 37 mg and 57 mg per day, respectively.49 Therefore, children consume about 4–5-fold more BLCFA than DHA + ARA per day.

An American adult approximately consumes 500 mg of BLCFA per day.20 This is also higher than the intake of DHA (80–100 mg/day).50 A cup (244 g) of yak milk contains about 669 mg BLCFA,19 which is higher than the same amount of whole milk (158 mg).21 Yak herders in Qinghai, China, roughly consume 3500–5000 mg of BLCFA daily,19 which is the highest in the world thus far (Figure 3).

Figure 3.

Figure 3

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Estimated intake of BLCFA and docosahexaenoic acid (DHA) at different life stages. Data were adapted from Sun et al.,19 Ran-Ressler et al.,20,49 and Whelan et al.50 There was no estimation regarding the daily DHA intake in the fetus and yak herders in Qinghai, China.

6. Absorption and Metabolism of BLCFA in Human Cells

The absorption of BLCFA by the intestine is affected by the branched-chain position and carbon chain length. In H4 cells, a nontransformed primary human fetal intestinal epithelial cell strain, the absorption efficiency of single BLCFA was in the order of anteiso-17:0 > iso-16:0 > iso-18:0 > iso-20:0.51 The uptake of iso-BLCFA is higher than anteiso-BLCFA in MCF-7 cells.52 Moreover, BLCFA can be incorporated into cellular monoacylglycerols (MAG), diacylglycerols (DAG), triglycerides (TAG), phospholipids (PL), cholesterol esters (CE), and free fatty acids (FFA). The incorporation of iso-16:0, anteiso-17:0, and iso-18:0 into H4 cell lipids was in the order of PL > TAG > CE > DAG > FFA > MAG.51 Compared to the BLCFA in the form of FFA, Caco-2 cells absorb BLCFA in MAG more easily.53 After absorption, BLCFA can be oxidized,9 and extended by ELOVL1, ELOVL3, ELOVL6, and ELOVL7.54,55 Meanwhile, FADS2 mediates the Δ6-desaturation of BLCFA.56 A recent review by Gozdzik et al. elaborated on the oxidation of BLCFA in mammals.9

Mammals can endogenously de novo synthesize a small amount of BLCFA from branched-chain amino acids (BCAA).57,58 However, this synthesis process is limited by enzymatic decarboxylation of ethylmalonyl-CoA and methylmalonyl-CoA.59 The de novo synthesis pathways of BLCFA in mammal tissues such as liver, muscle, and adipose tissues were described in detail by a review by He et al.7

7. Biological Activities of BLCFA

7.1. Cytotoxicity to Cancer Cells

BLCFA has displayed cytotoxicity to cancer cells both in vitro and in vivo. Table 2 is listing the in vitro and in vivo studies with BLCFA dosages, treatment time, and other information. Iso-15:0 is the most widely studied BLCFA in potential anticancer properties. In vivo, iso-15:0 has been shown to suppress prostate cancer, liver cancer, and T-cell non-Hodgkin lymphomas (T-NHL) in rodent xenograft models. In vitro, iso-15:0 has displayed cytotoxicity to multiple cancer cells including bladder cancer, leukemia, colon cancer, small cell lung cancer, pancreatic cancer, gastric cancer, and breast cancer cells. Also, anteiso-15:0 has shown toxic effects on prostate cancer, nonsmall cell lung cancer, and breast cancer cells. Besides, another BLCFA iso-17:0 has cytotoxic effects on MCF7 cells, a human breast cancer cell line.

Table 2. BLCFA Exert Cytotoxicity to Cancer Cells in Vitro and in Vivo.

BLCFA cancer types in vitro or in vivo animal model cell lines dosage treatment period ref
iso-15:0 prostate cancer in vivo MetaMouse orthotopic model   35, 70, and 105 mg/kg/day 43 days (61)
iso-15:0 prostate cancer in vitro   DU 145 0–60 μg/mL 48 h (61)
anteiso-15:0 prostate cancer in vitro   DU 145, PC3 0–120 μg/mL 72 h (65)
iso-15:0 liver cancer in vivo MetaMouse orthotopic model   70 mg/kg/day 40 days (61)
iso-15:0 Liver cancer in vitro   SNU-423 0–60 μg/mL 48 h (61)
iso-15:0 T-cell non-Hodgkin lymphomas in vivo BALB/c nude mice   70 mg/kg/day 15 days in EL4 cell xenografts; 30 days in Jurkat cell xenografts (60)
iso-15:0 T-cell non-Hodgkin lymphomas in vitro   Jurkat, Hut78, and EL4 0–80 μg/mL 24, 48, and 72 h (60)
iso-15:0 bladder cancer in vitro   T24, 5637, and UM-UC-3 0–140 μg/mL 12 and 24 h (62)
iso-15:0 leukemia in vitro   K-562 0–60 μg/mL 48 h (61)
iso-15:0 colon cancer in vitro   HCT 116 0–60 μg/mL 48 h (61)
iso-15:0 small cell lung cancer in vitro   NCI-H1688 0–60 μg/mL 48 h (61)
anteiso-15:0 nonsmall cell lung cancer in vitro   A549 0–120 μg/mL 72 h (65)
anteiso-15:0 nonsmall cell lung cancer in vitro   H1299 0–120 μg/mL 72 h (65)
iso-15:0 pancreatic cancer in vitro   BxPC-3 0–60 μg/mL 48 h (61)
iso-15:0 gastric cancer in vitro   NCI-SNU-1 0–60 μg/mL 48 h (61)
iso-15:0 breast cancer in vitro   MCF7 0–60 μg/mL 48 h (61)
iso-15:0 breast cancer in vitro   MCF7 50–400 μM 24, 48, and 72 h (52)
anteiso-15:0 breast cancer in vitro   MCF-7 0–120 μg/mL 72 h (65)
iso-15:0 breast cancer in vitro   SKBR-3 0.05–0.2 mM 24 h (63)
iso-15:0 breast cancer in vitro   SKBR-3 0–1 mM 72 h (64)
iso-17:0 breast cancer in vitro   MCF7 50–400 μM 24, 48, and 72 h (52)
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In mouse models, BLCFA inhibits the growth of tumors at doses of 35, 70, and 105 mg/kg/day, 70 mg/kg/day, and 70 mg/kg/day, respectively.60,61In vivo studies have shown BLCFA exert this cytotoxicity to cancer cells in three pathways, namely, promoting apoptosis, inhibiting fatty acid synthesis, and inducing cell cycle arrest (Figure 4). BLCFA cause cancer cell apoptosis mainly through the endogenous pathways, including the caspase-dependent pathway and apoptosis-inducing factor (AIF)-mediated caspase-independent pathway. Iso-15:0 induces apoptosis of T-NHL cell lines (Jurkat, Hut78, EL4 cells) by down-regulating AKT phosphorylation and activating the caspase pathway.60 Meanwhile, iso-15:0 causes apoptosis of human bladder cancer cell lines (T24, 5637, and UM-UC-3 cells) by inhibiting AKT phosphorylation and promoting mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 phosphorylation.62 Then cytochrome (Cyt C) is released into the cytoplasm, and this further activates the caspase pathway.62 In addition, iso-15:0 stimulates the AIF transfer from mitochondria to nuclei, resulting in the apoptosis of SKBR-3, a human breast cancer cell line that overexpresses the human epithelial growth factor receptor-2 (Her2) gene product.63 Fatty acid synthase (FASN) is considered to be a target for the development of anticancer drugs. Iso-15:0 not only inhibits FASN, acetyl-CoA carboxylase (ACC), and glucose-6-phosphate dehydrogenase (G6PDH) activity directly but also reduces the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) in SKBR-3 cells.64 Besides, iso-15:0 can constrain the growth of T-NHL cell lines by blocking the transition of cells from the G1 phase to the S phase.60 Similarly, anteiso-15:0 induces apoptosis of human prostate cancer cells PC3 by changing cell morphology, inducing DNA fragmentation and G2-M phase arrest, and activating caspase-3.65 Meanwhile, anteiso-15:0 inhibits the formation of 5-hydroxyeicosatetraenoic acid (5-HETE) in PC3 and RBL-1 cells, which is the key molecule in the growth and metastasis of prostate cancer cells.65 This activity is associated with the length of the main chain of BLCFA, and the type or position of the branched group.52,66

Figure 4.

Figure 4

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Mechanisms of iso-15:0 in cytotoxicity to cancer cells. (1) Inhibition of fatty acid synthesis through suppression of ACC, FASN, G6PDH, and NAPDH. (2) Enhancement of apoptosis in cancer cells through caspase-dependent pathway and AIF-mediated caspase-independent pathway. (3) Arrest of cell cycle by inhibiting the cell transition from G1 phase to S phase.

Human data are limited regarding BLCFA-induced potential antitumor property. A latest study observed an increase in serum iso-15:0 levels during 12 months of follow-up after resection in breast cancer patients.67 However, after 24 months, iso-15:0 level returned to the preoperative level.67 This may be associated with iso-15:0 triggering of apoptosis in breast cancer cells, thereby preventing the recurrence of the disease. Generally, these observations indicate that BLCFA, iso-15:0 in particular, may be a new clue for the development of anticancer agents, but more in-depth investigations are essential.

7.2. Anti-inflammation Effect

BLCFA are first known for their anti-inflammation effects because they can promote intestinal health in infants by alleviation of excess inflammation. Full-term infants had higher concentrations of BLCFA in vernix caseosa and meconium compared with premature infants.68 Necrotizing enterocolitis (NEC) is a common disease in premature infants with high morbidity and mortality.69 In a neonatal rat model, feeding formula prepared with 20% w/w BLCFA mixture reduces the incidence of NEC by 56% and up-regulates the expression of anti-inflammatory cytokines interleukin (IL)-10.70 BLCFA mitigate lipopolysaccharide (LPS)-induced inflammation in Caco-2 cells by down-regulating the expression of pro-inflammatory cytokines IL-8.71,72 Nuclear factor-κB (NF-κB) is the vital signaling pathway controlling the inflammation. The NF-κB protein family includes five members: RelA (p65), RelB, c-Rel, p50, and p52. Dimers are formed between different family members, with p50 and p65 being the most common. The activation of NF-κB pathway can be divided into the canonical and noncanonical pathway. In the canonical pathway, the p50–p65–IκB trimer exists in the cytoplasm in nonactivated state.73 At this time, IκB masks the nuclear localization sequence of NF-κB dimers and prevents it from entering the nucleus.73 When cells are stimulated by external stimuli, the IκB kinase (IKK) complex is activated, leading to IκB phosphorylation, ubiquitination, and degradation. As a result, NF-κB dimers are released.74 Then the NF-κB dimer is translocated from the cytoplasm to the nucleus and binds to the target genes to act as a transcription factor. Toll-like receptor 4 (TLR-4), a key molecule in the canonical pathway, mediates NF-κB activation. Mechanically, anteiso-13:0 and anteiso-15:0 may directly inhibit TLR4, then restrain the NF-κB signaling pathway and ultimately reduce the synthesis of IL-8 in Caco-2 cells (Figure 5).72 Differently, iso-18:0, iso-20:0, and anteiso-17:0 decrease NF-κB but not TLR-4 expression.72 Moreover, iso-14:0 and iso-16:0 do not inhibit the activity of NF-κB, but still reduce the expression of IL-8, indicating that other pathway exists in meditating downregulation of IL-8.72 In human adipocytes, iso-16:0 dose-dependently decrease the mRNA expression of pro-inflammatory genes cyclooxygenase-2 (COX-2), 15-lipoxygenase (ALOX-15), and IL-6.75 Following research is indispensable to uncover the other inflammatory signaling pathways that BLCFA will interfere with, for instance, the Janus kinase-signal transducer and activator of transcription (JAK-STAT), MAPK pathway.

Figure 5.

Figure 5

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Mechanisms of BLCFA in anti-inflammatory effect, modified from Yan et al.72Anteiso-13:0 and anteiso-15:0 suppress TLR4, NF-κB signaling, and IL-8 expression. Iso-18:0, iso-20:0 and anteiso-17:0 restrain NF-κB signaling and IL-8 expression. Iso-14:0 and iso-16:0 inhibit IL-8 expression.

7.3. Lipid-Lowering Activity

There is considerable evidence displaying the role of BLCFA in the regulation of lipid metabolism. Serum BLCFA levels are lower in morbidly obese patients than in lean people.76 Weight loss induced by bariatric surgery is associated with an increase in serum BLCFA.76 Besides, the BLCFA level returns to normal 6–9 months after surgery.77 However, BLCFA levels increase significantly in the liver of NAFLD patients.78 But whether this increase is the effect of the liver disease or the cause of the disease needs further investigation. Serum total iso-BLCFA are negatively correlated with circulating TAG and hepatic stearoyl-coenzyme A desaturase 1 (SCD1) activity in overweight patients, suggesting a possible role of BLCFA in regulating lipid metabolism.79 In a mouse model, high-protein diets promote the accumulation of BLCFA in the liver, and liver iso-16:0 and anteiso-17:0 levels are negatively correlated with hepatic TAG concentration.80 In a human L02 steatosis cell model, 0.25 mM iso-15:0 and 0.25 mM iso-18:0 both decrease intracellular TAG contents.81Iso-15:0 and iso-18:0 increase the mRNA levels of peroxisome proliferators-activated receptor α (PPARα), carnitine palmitoyltransferase 1 (CPT1), CPT2, and acyl-CoA oxidase 1 (ACOX1) and decrease protein levels of sterol regulatory element-binding protein 1c (SREBP-1c) and mRNA levels of FASN (Figure 6).81 In addition, a study using Caenorhabditis elegans also revealed that iso-17:0 could inhibit SREBP-1.82

Figure 6.

Figure 6

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Mechanisms of iso-15:0 and iso-18:0 in lipid-lowering activity. (1) Increasement of fatty acid oxidation by induction of PPARα, CPT1, CPT2, and ACOX1. (2) Inhibition of fatty acid synthesis by targeting SREBP-1c and FASN.

7.4. Reducing the Risk of Metabolic Disorders

There have been plenty of reports on the correlation analysis of endogenous BLCFA levels and metabolic disorders in humans. The prevalence of cardiometabolic disorders (CMD) has increased worldwide. Healthy eating patterns can reduce CMD.83 Therefore, it is of particular importance to prevent CMD through dietary intervention. A recent systematic review assessed the relationship between BLCFA in dairy products and CMD, and found that there was a beneficial association between circulating BLCFA and cardiac metabolic risk.6 Also, higher levels of serum BLCFA may be negatively correlated with obesity, insulin sensitivity, and inflammatory biomarkers.6 There is an inverse correlation between BLCFA levels in serum and adipose tissue and the metabolic syndrome (defined as a clinical condition involving the accumulation of metabolic risk factors, like abdominal obesity, high TAG levels, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, elevated blood pressure, and fasting hyperglycemia).8 Another study showed a longitudinal association between circulating BLCFA and cardiometabolic phenotypes underlying type 2 diabetes mellitus (T2DM).84 Specifically, iso-14:0, anteiso-14:0, iso-15:0, and anteiso-15:0 are potentially important.84 Also, the vast data on associations between dietary patterns and health benefits are worth revisiting to recognize the role that BLCFA is playing in.

7.5. Maintenance of Normal β Cell Function and Insulin Sensitivity

The occurrence of T2DM is often accompanied by insulin resistance (IR) and insulin secretion defects. Total BLCFA content in adipose tissue is positively correlated with insulin sensitivity in skeletal muscle cells of obese people.85 In addition, there is a strong correlation between the elevation of BCAA (precursor of BLCFA) and IR in mammals.86 Abnormal metabolism of BCAA contributes to the IR in obesity. BLCFA is likely to play a role therein. Under high glucose conditions, 10 μM iso-17:0 treatment for 48 h in INS-1 β-cell line can increase pancreatic and duodenal homeobox 1 (PDX1) protein levels, a crucial protein in pancreatic development, differentiation, and maturation of β cells and insulin secretion.87 The current data regarding BLCFA-mediated effects on β cell function and insulin sensitivity are limited and not comprehensive, appealing for more research to elucidate the exact mechanism.

7.6. Regulating Development

BLCFA are vital for the development of C. elegans.88,89Iso-17:0 is the key to the survival of C. elegans under high-glucose diet.90Iso-17:0 increased mechanistic target of rapamycin complex 1 (mTORC1) signal transduction, thereby increasing glucose uptake and metabolism, rather than by regulating cell membrane fluidity.90 Meanwhile, deficiency of iso-17:0-derived glucosylceramide leads to developmental stagnation in C. elegans.91 Zhu et al. further discovered that iso-17:0 mediated amino acid sensing upstream of mTORC1.92 Under dietary restriction (DR) condition, amino acid synthesis is reduced due to the weakened mTORC1 signaling, and C. elegans are thus arrested at the L3 stage.92 However, these worms will continue to develop into adults after the external environment improves.92 Notably, supplementation with iso-17:0 alone in DR condition leads to C. elegans abnormal death.92 This is because iso-17:0 enhances mTORC1 signaling, promotes de novo synthesis of proteins, and depletes the limited amino acids stored in the body (Figure 7).92 Thrillingly, this pathway is conserved among the mammalian species. When iso-17:0 is incubated the BCAA-deprived 3T3L1 cells, the phosphorylation of P70S6K (mTOR downstream target) is significantly enhanced, and this activation is completely inhibited by the mTORC1 inhibitor rapamycin.92 However, there have been no data in mammalian animals regarding BLCFA on developmental regulation thus far.

Figure 7.

Figure 7

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Mechanisms of iso-17:0 in regulating development, modified from Zhu et al.92 (1) Under BCAA-rich conditions, iso-17:0 activates the mTORC1 pathway, and Caenorhabditis elegans will develop to adults. (2) In the absence of BCAA, the mTORC1 signaling is down-regulated, and C. elegans will enter the L3 stage. (3) When BCAA are deficient and iso-17:0 is supplemented alone, the mTORC1 signaling is enhanced. Then the amino acid storage in body is depleted, and C. elegans will die.

7.7. Other Activities

BLCFA also have other biological activities, like mitigating focal ischemia-reperfusion injury and relieving corneal neovascularization.

Doses of 10, 40, and 80 mg/kg iso-15:0 have a protective effect in middle cerebral artery occlusion/reperfusion rat models.93 Apart from increasing blood flow in the infarct area, iso-15:0 also up-regulates the mRNA levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) (Figure 8).93

Figure 8.

Figure 8

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Mechanisms of BLCFA in maintaining β cells function and mitigating cerebral ischemia/reperfusion injury. (1) Iso-17:0 increases the level of PDX1, a key protein in pancreatic development, differentiation, and maturation of β cells and secretion of insulin. (2) Iso-15:0 increases the exprssions of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF).

Moreover, anteiso-15:0 has an advantage over dexamethasone in the treatment of corneal neovascularization.94Anteiso-15:0 is as effective as dexamethasone in reducing angiogenesis, but the number of neutrophil infiltration during treatment is significantly lower than dexamethasone.94 This effect can be ascribed to the decline of the 5-HETE by BLCFA, a proinflammatory metabolite of ARA.95

8. Summary and Prospect

BLCFA are widely distributed in common foods. Ruminant products and breast milk are rich sources of dietary BLCFA. BLCFA are inevitably consumed by humans at every stage of life. Fetus and infants ingest BLCFA from vernix caseosa and breast milk, respectively. Children and adults take in BLCFA mainly through ruminant products and other foods, such as fish and fermented food. The absorption and metabolism of BLCFA depend on their structures once they are in the human intestines. At present, data on the intake of BLCFA are limited to China and North America, lacking information on other countries and regions in the world. The reported biological functions of BLCFA include cytotoxicity to cancer cells, anti-inflammation, lipid-lowering activity, reducing the risk of metabolic disorders, maintaining normal β cell function and insulin sensitivity, regulating development, and mitigating cerebral ischemia/reperfusion injury. But the molecular mechanisms for BLCFA-mediated bioactivities have been preliminarily explored.

Based on the extensive food distributions and versatile biological activities, BLCFA will be promising functional nutrients, dietary supplements, and even pharmacologically active agents. Further in-depth studies are crucial to establish the epidemiology between BLCFA intake and health outcomes in humans and uncover the specific mechanistic pathways of their health promotion properties.

Acknowledgments

This research was supported by a grant from the Science and Technology Innovation Program of Hunan Province (Changsha, China, 2022RC1161), the Science Fund for Distinguished Young Scholars of Changsha City, China (Changsha, China, kq2206033), and the Natural Science Foundation of Hunan (Changsha, China, 2022JJ40169). Thanks to Figdraw (www.figdraw.com) for providing materials for the graphical abstract and Figures 4–8.

The authors declare no competing financial interest.

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