Description: <b>HCA</b> is a naturally occurring compound primarily known for its potential effects on appetite and lipid metabolism via inhibition of ATP citrate lyase.<br>
Derivative of citric acid that is found in a variety of tropical plants including Garcinia cambogia and Hibiscus sabdariffa<br>
Hydroxycitric acid (HCA) is a plant‐derived hydroxycinnamic acid derivative best known for inhibiting ATP citrate lyase (ACLY), a key enzyme that generates cytosolic acetyl-CoA from citrate for lipid and cholesterol synthesis. By reducing ACLY activity and downstream lipogenesis, HCA shifts cellular metabolism and can activate energy-sensing pathways (such as AMPK) in some models. Evidence for direct anticancer cytotoxicity is modest and often linked to metabolic stress rather than primary cytotoxic mechanisms. Oral exposure is influenced by rapid metabolism and conjugation, with systemic bioavailability often limited compared to levels used in many in vitro studies.<br>
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• Hydroxy-Citric Acid (HCA) is a compound extracted from Garcinia cambogia, primarily recognized for its potential effects on lipid metabolism and appetite suppression.<br>
• It has been proposed to inhibit the enzyme ATP citrate lyase, which is involved in converting citrate into acetyl-CoA—a key step in fatty acid synthesis.<br>
• By modulating lipid synthesis pathways, HCA has been studied in the context of obesity and metabolic disorders, with some exploratory research considering its implications in cancer metabolism.<br>
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• Inhibition of ATP Citrate Lyase (ACLY)******<br>
ACLY converts citrate into acetyl-CoA, a building block for fatty acid and cholesterol synthesis. Many cancer cells upregulate lipid synthesis to support membrane production and energy storage; hence, inhibiting ACLY presents a potential strategy to disrupt cancer cell metabolism.<br>
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• Impact on Lipogenesis<br>
Reduced acetyl-CoA production can impair de novo lipogenesis, potentially limiting the proliferation of rapidly dividing cells that have high lipid demands.<br>
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• Interactions with Other Metabolic Pathways (modulation of citrate levels may affect the TCA cycle)<br>
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-Dosages used in weight loss studies typically ranging from 500 mg to 1500 mg per day<br>
Human cyclists: 3.1 mL/kg body wt of an HCA solution (19 g/L) --> 248mg<br>
"Studies have shown that humans can safely ingest 13.5 g of hydroxycitrate per day with plasma levels of 82 mg/L (0.39 mM) achieved". Appetite suppression and weight loss effects are mixed.<br>
Typically, HCA used in dietary weight loss supplement is bound to calcium, which results in a poorly soluble (<50%) and less bioavailable form. Conversely, the structural characteristics of a novel Ca2+/K+ bound (-)-HCA salt (HCA-SX or Super CitriMax) make it completely water soluble as well as bioavailable.<br>
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-HydroxyCitrate (HCA) typically used in a dose of about 1.5g/day or more for cancer (inhibition of the Melavonate Pathway?)<br>
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<!-- Hydroxycitric Acid (HCA) — Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>ATP citrate lyase (ACLY) inhibition</td>
<td>ACLY ↓ (reported; model-dependent)</td>
<td>Energy metabolism modulation</td>
<td>P, R, G</td>
<td>Lipid synthesis constraint</td>
<td>HCA interferes with ACLY, reducing cytosolic acetyl-CoA used for lipogenesis; this is the most direct biochemical target supported in metabolic studies.</td>
</tr>
<tr>
<td>2</td>
<td>Fatty acid synthesis / lipogenesis pathways</td>
<td>FAS ↓; lipogenic genes ↓ (reported)</td>
<td>Lipid synthesis modulation</td>
<td>R, G</td>
<td>Metabolic shift</td>
<td>Downstream of ACLY inhibition; reduced fatty acid and cholesterol precursor synthesis is the central metabolic effect.</td>
</tr>
<tr>
<td>3</td>
<td>AMPK activation (energy sensor, model-dependent)</td>
<td>AMPK ↑ (reported)</td>
<td>Energy homeostasis support</td>
<td>R, G</td>
<td>Energy balance modulation</td>
<td>AMPK activation is observed in some in-vitro systems with HCA, linking energy stress to downstream metabolic effects.</td>
</tr>
<tr>
<td>4</td>
<td>Appetite / satiety signaling (neuropeptides)</td>
<td>—</td>
<td>Appetite modulation (reported)</td>
<td>G</td>
<td>Metabolic/behavioral</td>
<td>Some human studies suggest appetite/satiety modulation but evidence is mixed; include as “reported” not primary anticancer mechanism.</td>
</tr>
<tr>
<td>5</td>
<td>Insulin / glucose metabolism signaling</td>
<td>Modulation reported (trend) </td>
<td>Insulin sensitivity influence (reported)</td>
<td>G</td>
<td>Metabolic adjustment</td>
<td>Some systematic models report modest effects on insulin and glucose handling; these are downstream metabolic observations, not direct anticancer targets.</td>
</tr>
<tr>
<td>6</td>
<td>NF-κB inflammatory transcription</td>
<td>Modest ↓ reported (context)</td>
<td>Inflammation modulation (reported)</td>
<td>R, G</td>
<td>Anti-inflammatory trend</td>
<td>Some preclinical models link metabolic improvement to reduced inflammation; not a robust anticancer signal alone.</td>
</tr>
<tr>
<td>7</td>
<td>Cell proliferation / apoptosis</td>
<td>Modulation reported in some tumor models</td>
<td>↔</td>
<td>G</td>
<td>Conditional growth modulation</td>
<td>Isolated in vitro studies show modest proliferation changes; evidence is far weaker and often linked to metabolic stress rather than direct cytotoxicity.</td>
</tr>
<tr>
<td>8</td>
<td>PI3K/AKT / survival kinase signaling</td>
<td>Reported modulation (weak / context)</td>
<td>↔</td>
<td>R, G</td>
<td>Growth signaling adaptation</td>
<td>Reported downstream of metabolic modulation in some models; not a primary target like ACLY.</td>
</tr>
<tr>
<td>9</td>
<td>Invasion / metastasis programs (MMPs / EMT)</td>
<td>Reports exist but inconsistent</td>
<td>↔</td>
<td>G</td>
<td>Phenotype outcomes</td>
<td>Largely phenotype-level readouts in select cell lines; not a consistent mechanistic anchor.</td>
</tr>
<tr>
<td>10</td>
<td>Bioavailability / metabolism constraint (rapid conjugation; limited systemic exposure)</td>
<td>Systemic exposure variable; phase II metabolism</td>
<td>—</td>
<td>—</td>
<td>Translation constraint</td>
<td>HCA is absorbed but rapidly metabolized/conjugated; systemic levels after oral intake are relatively low compared to many in vitro assay doses.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (rapid biochemical effects such as ACLY engagement)</li>
<li><b>R</b>: 30 min–3 hr (acute metabolic signaling / transcription shifts)</li>
<li><b>G</b>: >3 hr (transcriptional adaptation and phenotype outcomes)</li>
</ul>