Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are newly identified endogenous lipids regulated by fasting and high-fat feeding and associated with insulin sensitivity. Structurally, these esters are comprised of a C-16 or C-18 fatty acid (e.g., palmitoleic, palmitic, oleic, or stearic acid) linked to a hydroxylated C-16 or C-18 lipid. 9-PAHSA is a FAHFA in which palmitic acid is esterified to 9-hydroxy stearic acid. PAHSAs are the most abundant forms of FAHFA in serum as well as white and brown adipose tissues of glucose tolerant AG4OX mice, which overexpress Glut4 specifically in adipose tissue. 9-PAHSA is the predominant isomer of PAHSA in wild type and AG4OX mice. It is found in humans and is reduced in the serum and adipose tissues of insulin-resistant humans. 9-PAHSA improves glucose tolerance, stimulates insulin secretion, and has anti-inflammatory effects in mice.
9-PAHSA is an orally active endogenous GPR120 agonist (EC50=18 μM). 9-PAHSA significantly inhibits LPS-induced inflammatory responses by blocking the NF-κB pathway. 9-PAHSA induces adipocyte browning, enhances glucose uptake and reduces lipid accumulation, while improving mitochondrial function and the survival rate of steatotic hepatocytes. In terms of neuroprotection, 9-PAHSA regulates the expression of REST and BDNF in the prefrontal cortex of diabetic mice, and effectively prevents spatial working memory deficits and abnormal social behaviors. 9-PAHSA does not directly regulate insulin secretion or improve systemic insulin sensitivity, and possesses specific anti-inflammatory, metabolic regulatory and neuroprotective properties. 9-PAHSA can be used in the research of diabetes-related cognitive impairment, obesity and non-alcoholic fatty liver disease.
体外研究
(R) 9-PAHSA and (S) -9-PAHSA (20 μM; 30 min pre incubation) do not significantly increase the basal or insulin stimulated glucose uptake of differentiated adipocytes in vitro [1].
Racemic 9-PAHSA (1-20 μM; 2 h) does not stimulate glucose dependent insulin secretion in dispersed mouse islets [1].
9-PAHSA (5-30 μM; 72 h) showed no significant cytotoxicity on 3T3-L1 preadipocytes after 72 h treatment.
9-PAHSA (5-10 μM; 6 h) can increase the survival rate of steatotic HepG2 cells, with a relative survival rate of up to 140% observed in cells treated with 500 μM oleic acid, while higher concentrations of 9-PAHSA can reduce cell survival rate.
9-PAHSA (10-40 μM; 6 h) can reduce lipid accumulation in oleic acid-induced steatosis HepG2 cells.
Cell Viability Assay
Cell Line:
HepG2
Concentration:
5 μM, 10 μM, 20 μM, 40 μM; tested in cells pre-treated with 250 μM, 500 μM, or 1000 μM oleic acid
Incubation Time:
6 hours
Result:
Increased relative cell viability to up to 120% in HepG2 cells treated with 250 μM oleic acid at 5 μM, while reduced viability at 10 μM, 20 μM, and 40 μM.
Increased relative cell viability to up to 140% in HepG2 cells treated with 500 μM oleic acid at 5 μM and 10 μM, while reduced viability at 20 μM and 40 μM.
Increased relative cell viability slightly in HepG2 cells treated with 1000 μM oleic acid at 5 μM and 10 μM, while reduced viability at 20 μM and 40 μM.
体内研究
9-PAHSA (22.5 mg/kg; gavage; Single dose acute administration did not improve glucose tolerance or stimulate insulin or GLP-1 secretion in male C57BL/6J mice fed with VS-LFD or VS-HFD for 18 weeks [1].
9-PAHSA (45 mg/kg; gavage; Single acute administration did not improve glucose tolerance or stimulate insulin or GLP-1 secretion in male C57BL/6J mice fed with BT-HFD for 18 weeks [1].
9-PAHSA (15 mg/kg; gavage; Single acute administration did not improve glucose tolerance or stimulate glucose dependent insulin secretion in male C57BL/6J mice fed with LARD-HFD for 20 weeks [1].
9-PAHSA (50 mg/kg; gavage; Daily; 28 days) can improve the cognitive impairment related to type 2 diabetes in db/db mice by reducing the expression of REST in mouse cortex and up regulating the expression of BDNF in cortex, while restoring spatial working memory and social novelty preference [2].
9-PAHSA (50 mg/kg; oral administration; Once a day; Continuous for 28 days) can promote browning of subcutaneous white adipose tissue in wild-type and ob/ob mice by upregulating brown adipose specific genes and proteins, with a more significant effect in ob/ob mice [3].
Animal Model:
C57BL/6J mice with Type 2 diabetes (male; 18-week diet-induced obesity via BT-HFD feeding)
Dosage:
45 mg/kg
Administration:
oral gavage; single acute dose
Result:
Increased plasma levels significantly to around 145 nM.
Detected no significant differences in glucose excursion during oGTT, baseline insulin secretion, glucose-stimulated insulin secretion, or active GLP-1 release compared to vehicle-treated mice.
Did not significantly alter body weight or food intake in either WT or ob/ob mice.
Reduced triglyceride levels (no specific numerical value provided).
Significantly increased mRNA expression of brown fat-specific markers UCP1, PGC1α, Cidea, and PRDM16 in sWAT, with greater increases observed in ob/ob mice compared to WT mice.
Significantly elevated protein levels of UCP1 and PGC1α in both mouse strains.
Induced smaller, multilocular fat cells in sWAT of treated mice via H&E staining.
Increased UCP1 and PGC1α staining in sWAT via immunohistochemistry.
分子式
C34H66O4
分子量
538.9
CAS号
1481636-31-0
中文名称
9-[(1-oxohexadecyl)oxy]-octadecanoicacid
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Powder
-20°C
3 years
4°C
2 years
In solvent
-80°C
6 months
-20°C
1 month
溶解性数据
In Vitro:
DMSO : 5 mg/mL (9.28 mM; ultrasonic and warming and heat to 80°C)