ABSTRACT
Objective To find novel genes related to maturity-onset diabetes of the young(MODY)or novel muta-tions of known MODY related genes and provide the basis for MODY diagnosis. Methods Taking the major clinical features of MODY as screening criteria,we selected four patients from the Endocrine Department of Peking Union Medical College Hospital and prepared their genomic DNA sample for whole exome sequencing.PCR and Sanger se-quencing are used to validate the sequencing results. Results Two novel mutations of the GCK gene and HNF4α gene, c.1348G>T(p.Ala450Thr)and c.758G>A(p.Arg253Gln)were found in two patients. Conclusions These two patients are both MODY patients and this is the first time the novel mutations were found.
ABSTRACT
The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4) plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and activity of HNF4is regulated by diverse hormonal and signaling pathways such as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming growth factor-, estrogen, and cytokines. HNF4appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver. There have been a few reviews on the regulation of drug metabolism, lipid metabolism, cell proliferation, and inflammation by HNF4. However, the knowledge on how the expression and transcriptional activity of HNF4is modulated remains scattered. Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4, and how HNF4crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.
ABSTRACT
Objective To investigate the expression of hepatocyte nuclear factor-1α (HNF-1α) and hepatocyte nuclear factor-4α (HNF-4α) in human hepatocellular carcinoma (HCC) and explore the function of HNF-1α and HNF-4α during HCC carcinogenesis and development. Methods Twenty-six specimens of hepatocellular carcinoma were collected. The expressions of HNF-1α and HNF-4α in HCC tissues and adjacent non-cancerous tissues were detected by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry staining. Results The mRNA levels of HNF-1α and HNF-4α were significantly lower in HCC tissues than that in adjacent non-cancerous tissues (0.818±0.371 vs. 0.383±0.102 for HNF-1α, P＜0.05;0.846±0.384 vs. 0.397±0.105 for HNF-4α, P＜0.05).The positive rates of HNF-1α and HNF-4α protein were significantly lower in HCC tissues than in adjacent non-cancerous tissues (92.3% vs. 42.3% for HNF-1α, P＜0.05;96.2% vs. 50.0% for HNF-4α, P＜0.05). The mRNA and protein expressions of HNF-1α and HNF-4α were correlated with tumor differentiation (P＜0.05). There was a negative correlation between HNF-1α and HNF-4α mRNA expressions in HCC tissues.Conclusion The expressions of HNF-1α and HNF-4α are down-regulated in HCC, which might be related to carcinogenesis and development of HCC.
ABSTRACT
The effects of berberine on the expression of hepatocyte nuclear factor-4α (HNF-4α) in liver of rats with fructose-induced insulin resistance and the molecular mechanism of berberine preventing insulin resistance were investigated. The experimental animals were divided into two groups of 16 animals each. The control group received a control routine diet containing 60% carbohydrate, and the study group a high-fructose diet containing 60% fructose as the sole source of carbohydrate. At the end of 6 weeks these were each subdivided into two groups. One was administered with berberine [187.5mg/(kg·d) in 5g/L carboxymethyl cellulosel] by intragastric intubation and the other group was treated with a vehicle (5g/L carboxymethyl cellulose). The rats were fed on the same dietary regimen for the next 4 weeks. After the experimental period of 10 weeks, plasma glucose, insulin and triglyceride levels were measured. HOMA insulin resistance index (HOMA-IR) was assayed. Immunohistochemistry, semiquantitative RT-PCR and western blot were used to detect the expression of HNF-4α in liver. Compared with control diet, fructose feeding induced hyperinsulinemia, HOMA-IR and increased triglyceride (all P<0.01). Berberine prevented the rise in plasma insulin (P<0.01), HOMA-IR (P<0.01) and triglyceride (P<0.05) in the fructose-fed rats. No change in plasma glucose was seen among these groups. The mRNA and protein expression of HNF-4α was decreased in the fructose-fed rats, but berberine could promote its expression. It was concluded that berberine could prevent fructose-induced insulin resistance in rats possibly by promoting the expression HNF-4α in liver.