While there appears to be no significant difference in the responses triggered by activation of cells expressing the HCA2 homodimer versus the HCA2/HCA3 heterodimer proteins, more studies are needed to confirm this.

[36] Lipolysis is the metabolic pathway in which triglycerides are hydrolyzed, i.e., enzymatically broken down, into their component free fatty acids and glycerol.

Furthermore, the HCA2-activating drug, MK-1903, when taken orally by healthy volunteers in phase 1 and 2 clinical trials, dramatically lowered their plasma free fatty acids levels.

In a murine ApoE−/− model of atherosclerosis, mice were feed a cholesterol‐rich (i.e., atherosclerosis-promoting) diet concurrently with β-hydroxybutyric acid, nicotine, or salt water daily for 9 weeks.

These results indicate that the anti-inflammatory and anti-atherosclerotic effects of β-hydroxybutyric acid in ApoE−/− mice depend on bone‐marrow‐derived HCA2-expressing cells, possibly M1 macrophages.

β-Hydroxybutyric acid did not reduce the brain damage or improve corner test performance in Hca2 gene knockout mice.

And, mice feed a ketogenic diet for 14 days (which increased their plasma levels of β-hydroxybutyric acid) also had reductions in the size of their brains' damaged sites.

Further studies indicated that the effect of niacin in reducing the size of damage brain sites involved the stimulation of HCA2-bearing monocytes and/or macrophages to produce prostaglandin D2.

[41]) Finally, several other studies, while not examining Hcar2 gene knockout or knockdown animals, reported that β-hydroxybutyric acid, niacin.

Compared to placebo-treated mice, β-hydroxybutyric acid-mice showed better performances in cognitive/memory testing; lower brain levels of the pro-inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and interleukin-6; lower levels of brain amyloid-beta precursor protein and amyloid-β protein; and higher levels of neprilysin, an enzyme that degrades amyloid proteins and is essential to prevent Alzheimer's disease in mice (i.e., mice lacking a functional gene that encodes neprilysin develop Alzheimer's disease-like symptoms).

)[42] In a third study, 5XFAD control mice that had normal levels of HCA2 or had their Hca2 gene knocked out were treated with a FDA-approved formulation of niacin, Niaspan.

Compared to mice not treated with MPTP, mice treated with MPTP followed by salt water developed defective motor functions as defined in three different tests, lower dopamine levels in their corpus striatum, activation of the microglia in their substantia nigra, and evidence of systemic inflammation (i.e., increased serum levels of the pro-inflammatory cytokines, tumor necrosis factor-α and interleuken-6).

[5] Although it is now regarded as one of the front-line (i.e. first used) therapies for treating this disease, dimethyl fumarate's mechanism of action, including its impact on HCA2 in human multiple sclerosis, has not yet been defined[31] and needs to be study.

Excessive activation of these neurons caused by inflammation stimulates the production of pro-inflammatory cytokines (e.g., interleukin-2 and tumor necrosis factor-α) and persistent nociplastic pain.

[48] Numerous studies in mice and rats have reported that β-hydroxybutyric acid, dimethyl fumarate, and MK-1903 have analgesic effects in models of thermal and mechanical hypersensitivity due to tibial bone fracture, intervertebral disc degeneration, complete Freund's adjuvant-induced arthritis, systemic lupus erythematosus, and chronic constriction of the sciatic nerve.

[13] In the mouse model of pain induced by chronic constriction of the sciatic nerve, the pain-relieving effects of β-hydroxybutyric acid and dimethyl fumarate did not occur in Hca2 gene knockout mice.

In a murine model of mastitis, post-pregnant female mice drank niacin-containing or normal water for 26 days and then received lipopolysaccharide injections into the fourth pair of their mammary glands.

Mouse fed pure water had extensive inflammation of their lipopolysaccharide-injected mammary glands, elevated mammary gland levels of pro-inflammatory cytokines (i.e., interleukin-6, interleukin-1β, and tumor necrosis factor-α), severe structural abnormalities such as thickened walls around their breasts' milk-producing alveoli, and breakdown of the blood-milk barrier which prevents uncontrolled exchange of components between the blood and alveolar milk.

[20] HCA2 may play a similar role in bovines: dairy cows with mastitis that were fed niacin for 7 days showed decreases in their serum and milk levels of pro-inflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-6, and interleukin-1β) and fewer cells in their milk compared to cows with mastitis that were not treated with niacin.

In human studies, the concentration of β-hydroxybutyric acid in the livers of ten patients with alcoholic hepatitis was significantly lower than that of normal individuals.

[22] Colon cancer, even if not preceded by an inflammatory bowel disease, commonly shows the presence of the inflammation response that is mounted to fight invading intestinal microorganisms.

In a murine model of colitis, rats were given niacin or water for 2 weeks, given daily rectal injections of the colitis-inducing agent, iodoacetamide, and sacrificed on day 15.

Compared to water-treated rats, niacin-treated rats developed milder colitis as defined by less declines in body weight, less declines in colon weights, and less rises in colon tissue levels of myeloperoxidase, an indicator of inflammatory cell (i.e. polymorphonuclear leukocytes) infiltration.