4-Hydroxyisoleucine

4-Hydroxyisoleucine ameliorates fatty acid-induced insulin resistance and inflammatory response in skeletal muscle cells.[Pubmed: 25109277]

Mol Cell Endocrinol. 2014 Sep;395(1-2):51-60.

The 4-Hydroxyisoleucine (4-HIL), an unusual amino acid isolated from the seeds of Trigonella foenum-graecum was investigated for its metabolic effects to ameliorate free fatty acid-induced insulin resistance in skeletal muscle cells.
METHODS AND RESULTS:
An incubation of L6 myotubes with palmitate inhibited insulin stimulated-glucose uptake and -translocation of glucose transporter 4 (GLUT4) to the cell surface. Addition of 4-Hydroxyisoleucine strongly prevented this inhibition. We then examined the insulin signaling pathway, where 4-Hydroxyisoleucine effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (PKB/AKT), AKT substrate of 160 kD (AS160) and glycogen synthase kinase 3β (GSK-3β) in L6 myotubes. Moreover, 4-Hydroxyisoleucine presented strong inhibition on palmitate-induced production of reactive oxygen species (ROS) and associated inflammation, as the activation of NF-κB, JNK1/2, ERK1/2 and p38 MAPK was greatly reduced. 4-Hydroxyisoleucine also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in the presence of palmitate, leading to enhanced insulin sensitivity.
CONCLUSIONS:
These findings suggested that 4-Hydroxyisoleucine could inhibit palmitate-induced, ROS-associated inflammation and restored insulin sensitivity through regulating IRS-1 function.

4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway.[Pubmed: 25454462]

Fitoterapia. 2014 Dec;99:307-17.

4-Hydroxyisoleucine (4-HIL) is an unusual amino acid isolated from fenugreek seeds (Trigonella foenum graecum L). Various studies have shown that it acts as an antidiabetic agent yet its mechanism of action is not clear.
METHODS AND RESULTS:
We therefore investigated the effect 4-Hydroxyisoleucine on the high fructose diet fed streptozotocin induced diabetic rats and L6 myotubes. 4-Hydroxyisoleucine (50 mg/kg) has improved blood lipid profile, glucose tolerance and insulin sensitivity in a diabetic rat model. It has increased the glucose uptake in L6 myotubes in AMPK-dependent manner and upregulated the expression of genes (PGC-1α, PGC-1β, CPT 1 and CPT 2), which have role in mitochondrial biogenesis and energy metabolism in the liver, skeletal muscles as well as in L6 myotubes. Interestingly, it also increased the AMPK and Akt expression along with their phosphorylated forms in the liver and muscle tissues of treated animals.
CONCLUSIONS:
Altogether we concluded that 4-Hydroxyisoleucine acts to improve insulin resistance by promoting mitochondrial biogenesis in high fructose diet fed STZ induced diabetic rats.

4-hydroxyisoleucine an unusual amino acid as antidyslipidemic and antihyperglycemic agent.[Pubmed: 16246556 ]

Bioorg Med Chem Lett. 2006 Jan 15;16(2):293-6.

Trigonella foenum-graecum, commonly known as fenugreek, is an annual herbaceous plant.
METHODS AND RESULTS:
From the seeds of T. foenum-graecum an unusual amino acid, 4-Hydroxyisoleucine 5, has been isolated, which significantly decreased the plasma triglyceride levels by 33% (P<0.002), total cholesterol (TC) by 22% (P<0.02), and free fatty acids by 14%, accompanied by an increase in HDL-C/TC ratio by 39% in the dyslipidemic hamster model.

In vitro anti-hyperglycemic activity of 4-hydroxyisoleucine derivatives.[Pubmed: 25636873]

Phytomedicine. 2015 Jan 15;22(1):66-70.

The nonproteinogenic amino acid, 4-Hydroxyisoleucine (1) has been isolated in large quantities from the fenugreek (T. foenum-graecum) seeds.
METHODS AND RESULTS:
Few novel derivatives (3-11 and 13-18) were prepared from the naturally occurring 4-Hydroxyisoleucine (1) and screened for their in vitro glucose uptake stimulatory effect in L-6 skeletal muscle cells.
CONCLUSIONS:
The derivatives 6, 7, 8, 10 and 11 exhibited better glucose uptake stimulatory activity than parent compound, 4-Hydroxyisoleucine at 5 and 10μM concentrations and compounds 7 and 11 enhanced translocation of insulin sensitive glucose transporters-4 in skeletal muscle cells.

Antidepressant-like effect of 4-hydroxyisoleucine from Trigonella foenum graecum L. seeds in mice.[Reference: WebLink]

Biomed. Aging Pathol., 2012, 2(3):121-5.

Trigonella foenum graecum L. (Fabaceae), also known as fenugreek, is one of the oldest medicinal plants, and has a long history of medical use in traditional and modern literature. 4-Hydroxyisoleucine (4-HI) constitutes about is 80% of the total content of free amino acids in Trigonella foenum graecum seeds.
METHODS AND RESULTS:
In present study, we report antidepressant-like effects of 4-HI in animal models of depression. The effects of 4-HI (10, 30 or 100 mg/kg) in Forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitches, and spontaneous motor activity (SMA) scores were assessed in mice. Oral acute administration of 4-HI showed the dose-dependent reversal in forced swim induced increased immobility behavior in normal and reserpinized mice in dose range of 3 to 30 mg/kg. The SMA scores were not affected by 4-HI in normal or reserpinized mice except for dose of 30 mg/kg, showing central rather than peripheral mechanism of 4-HI. Further, significant increase in number of 5-HTP (precursor of serotonin) induced head twitches was shown by 4-HI.
CONCLUSIONS:
In conclusion, 4-HI showed antidepressant-like effects in animal models of depression by brain serotonin turnover enhancement.

Microbiologyopen. 2013 Jun;2(3):471-81.

A novel l-isoleucine-4'-dioxygenase and l-isoleucine dihydroxylation cascade in Pantoea ananatis.[Pubmed: 23554367 ]

A unique operon structure has been identified in the genomes of several plant- and insect-associated bacteria. The distinguishing feature of this operon is the presence of tandem hilA and hilB genes encoding dioxygenases belonging to the PF13640 and PF10014 (BsmA) Pfam families, respectively.
METHODS AND RESULTS:
The genes encoding HilA and HilB from Pantoea ananatis AJ13355 were cloned and expressed in Escherichia coli. The culturing of E. coli cells expressing hilA (E. coli-HilA) or both hilA and hilB (E. coli-HilAB) in the presence of l-isoleucine resulted in the conversion of l-isoleucine into two novel biogenic compounds: l-4'-isoleucine and l-4,4'-dihydroxyisoleucine, respectively. In parallel, two novel enzymatic activities were detected in the crude cell lysates of the E. coli-HilA and E. coli-HilAB strains: l-isoleucine, 2-oxoglutarate: oxygen oxidoreductase (4'-hydroxylating) (HilA) and l-4'-hydroxyisoleucine, 2-oxoglutarate: oxygen oxidoreductase (4-hydroxylating) (HilB), respectively. Two hypotheses regarding the physiological significance of C-4(4')-hydroxylation of l-isoleucine in bacteria are also discussed.
CONCLUSIONS:
According to first hypothesis, the l-isoleucine dihydroxylation cascade is involved in synthesis of dipeptide antibiotic in P. ananatis. Another unifying hypothesis is that the C-4(4')-hydroxylation of l-isoleucine in bacteria could result in the synthesis of signal molecules belonging to two classes: 2(5H)-furanones and analogs of N-acyl homoserine lactone.