Homeostasis of Glucose and Lipid in Non-Alcoholic Fatty Liver Disease

Abstract

Industrialized society-caused dysregular human behaviors and activities such as overworking, excessive dietary intake, and sleep deprivation lead to perturbations in the metabolism and the development of metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, affects around 30% and 25% of people in Western and Asian countries, respectively, which leads to numerous medical costs annually. Insulin resistance is the major hallmark of NAFLD and is crucial in the pathogenesis and for the progression from NAFLD to non-alcoholic steatohepatitis (NASH). Excessive dietary intake of saturated fats and carbohydrate-enriched foods contributes to both insulin resistance and NAFLD. Once NAFLD is established, insulin resistance can promote the progression to the more severe state of liver endangerment like NASH. Here, we review current and potential studies for understanding the complexity between insulin-regulated glycolytic and lipogenic homeostasis and the underlying causes of NAFLD. We discuss how disruption of the insulin signal is associated with various metabolic disorders of glucoses and lipids that constitute both the metabolic syndrome and NAFLD.

Keywords: glucose; lipid; non-alcoholic fatty liver disease.

Figure 1

The hepatic metabolism of lipid and carbohydrate through insulin induced transcriptional regulation and circadian clock. Insulin signals and insulin-induced regulators: The schematic depicts the synergistic action of insulin and glucose in regulating lipogenesis in the liver and adipose tissue. Most of the insulin-mediated metabolic actions are controlled by the PI3K-AKT/PKB pathway. Under insulin stimulation, glycogenolysis is inhibited by activating PP1 and phosphodiesterase. Insulin activates the transcription of Srebp-1c and the proteolytic processing of SREBP-1c protein. The insulin-induced Srebp-1c transcription is facilitated by LXR and SREBPs themselves. LXR promotes lipogenesis not only primarily by increasing Srebp-1c expression, but also directly activate the promoters of Chrebp and some lipogenic genes. ChREBP is also activated by glucose signal by multiple mechanisms for the further progression of lipogenesis. Metabolism of glucose and lipid: After diet, vascular endothelium in adipose tissue absorbs and hydrolyzes triglycerides into non-esterified fatty acids by insulin-activated lipoprotein lipase. As released fatty acids are conveyed into adipocyte by fatty acids transporters, fatty acids are then re-esterified using glycerol 3-phosphate derived from glucose as a backbone to form triglycerides and stored as lipid droplets. Whereas fasting will promote lipolysis to convert triglycerides within lipid droplets into free fatty acid which is then uptook by hepatocytes for energy production. Insulin also promotes the absorption of glucose transporter to the plasma membrane of adipocyte for glucose uptake. However, insulin resistance causes the accelerated lipolysis in adipose tissue inappropriately and enhances hepatic glucose production through glycogenolysis, which further upregulates hepatic de novo lipogenesis and contributes to a critical biochemical pathway for the pathogenesis of NAFLD. Cross-talk between insulin and circadian clock: Growing evidences show a strong link between circadian clock with energy homeostasis. Hepatic circadian clock is regulated by insulin and altered by insulin resistance. In turn, circadian clock plays an essential role for regulating insulin secretion in the pancreas and balancing blood sugar levels. Insulin-induced regulators, such as SREBP-2, ChREBP, and lipogenic genes, also are directly targeted by circadian clock that drives the rhythmic expression of master regulators and rate-limiting enzymes of key hepatic metabolic outputs.