Endocrine pharmacologyHNF-4α regulated miR-122 contributes to development of gluconeogenesis and lipid metabolism disorders in Type 2 diabetic mice and in palmitate-treated HepG2 cells
Graphical abstract
Introduction
The latest Diabetes Atlas, the IDF estimate that the 415 million with diabetes and 318 million people have impaired glucose tolerance, and about 21 million women have developed gestational diabetes. And in 2015, about five million people have died from diabetes and its complications. Diabetes mellitus is a serious, complex metabolic disorder affecting approximately 4% of the population worldwide and the incidence is expected to increase to 5.4% of the population by 2030 (Wild et al., 2004). Although high blood glucose is the main characteristic of diabetic patients, most diabetics exhibit disorders of lipid metabolism (Assmann, 1991). In fact, several studies support treatment of the gluconeogenesis and lipid metabolism disorders in diabetes (Boussageon et al., 2014, Burden, 2003, Conget Donlo and Gimenez Alvarez, 2009, DeCoster, 2008). Hence, studies on the mechanism of the regulation of hepatic gluconeogenesis and lipid metabolism alterations in diabetes are highly warranted.
Hepatocyte nuclear factor-4α(HNF-4α) is a highly conserved member of the nuclear receptor superfamily and initially identified as a transcriptional factor required for liver-specific gene expression and regulation of hepatocyte differentiation (Sladek et al., 1990; Zaret, 2002). In addition, HNF4α was shown to be central to the maintenance of hepatocyte differentiation through regulation of genes involved in the control of lipid homeostasis in vivo (Hayhurst et al., 2001). HNF-4α activates the expression of PEPCK and G6Pase by binding to HNF-4α-binding cis-elements in their promoters (Zhang et al., 2012). Crucial roles of HNF-4α in nutritional regulation of these genes, and thus gluconeogenesis, were confirmed by analysis of liver-specific HNF-4α knockout in mice (Li et al., 2000). In addition, HNF-4α dysfunction has been implicated in mature onset diabetes of the young (MODY), Type 1 and Type 2 diabetes mellitus, high serum lipid levels, chronic kidney failure and the metabolic syndrome (Mitchell et al., 2002, Pruhova et al., 2003, Stoffel and Duncan, 1997). Thus, HNF-4α might be a key regulator in the pathogenesis of these disorders.
Micro RNAs (miRNAs) are a class of short non-coding RNAs (19–22 nucleotides) which act as post-transcriptional modulators of gene expression and have been shown to be regulate lipid metabolism and glycan biosynthesis (Karolina et al., 2012, Wilfred et al., 2007, Ye et al., 2013). The miR-122 has been identified as a critical regulator of hepatic gene expression and comprises more than 70% of the miRNA of the liver (Lagos-Quintana et al., 2002). Dysregulation of miRNA expression occur in liver cancer and in hepatitis (Esau et al., 2006, Fukuhara and Matsuura, 2013). In addition, miR-122 is implicated in several important aspects of liver pathobiology, including lipid metabolism, hepatocarcinogenesis, and HCV replication (Oliveira et al., 2015). Inhibition of miR-122 expression in mice resulted in down-regulation of cholesterol and lipid-metabolizing enzymes (Krutzfeldt et al., 2005). HNF-4α was shown to regulate miR-122 expression in both Huh7 cells and in mouse liver (Li et al., 2011). Thus, it can be surmised that HNF-4α is a crucial regulator of lipid metabolism and gluconeogenesis. It is unclear if HNF-4α regulated miR-122 is involved in the pathogenesis of the gluconeogenesis and lipid metabolism disorders observed in the Type 2 diabetic liver. In the present study, we examined if miR-122 contributed to HNF-4α-mediated down regulation of gluconeogenesis and lipid metabolism in Type 2 diabetic mice and in palmitate-treated HepG2 cells.
Section snippets
Materials
HepG2 cells were obtained from ATCC, Manassas, VA, USA. STZ was obtained from Sigma Chemical Co., St. Louis, MO, USA. Glucose, total cholesterol (TC), triglyceride (TG) diagnostic test kits were purchased from BioSino Bio-technology and Science Inc., Beijing, China. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) test kits were purchased from Nanjing Jiancheng Medical Bioengineering
Biochemical parameters and liver morphology are altered in diabetic mice
Initially, we examined the blood biochemical parameters in Control, DM animals. In DM animals, FBG was significantly higher and FINS significantly lower compared to Control (Table 2). The ISI calculated from fasting blood glucose and insulin level indicated the presence of insulin resistance in these diabetic mice. The OGTT indicated that plasma glucose in the DM animals was higher compared to Control animals at all times examined. The area under the glucose concentration curve (AUC) was
Discussion
The liver plays a crucial role in glucose and lipid homeostasis and disturbances in liver function alters glucose and lipid balance in the body. Dysfunction of liver signaling and metabolism may cause predisposition to Type 2 diabetes (Mueting, 1962). There are multiple cellular signals that regulate glucose, lipid and amino acid metabolism in the liver (Fan et al., 2011, Meng et al., 2013). HNF-4α is a member of the non-steroid nuclear receptor family and plays a key role in control of glucose
Disclosure statement
The authors have no disclosures.
Funding
This work was conducted in Preclinical Pharmacology R&D Center of Jilin Province and Key Lab of Traditional Medicine for Diabetes of Jilin Province. This work was supported by National Natural Science Foundation of China (81200598), Young Scholars Program of Norman Bethune Health Science Center of Jilin University (2013201011), and the Heart and Stroke Foundation of Canada. G.M.H. is a Canada Research Chair in Molecular Cardiolipin Metabolism.
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The first two authors contributed equally to this work and considered co-first author.