Question

2.Briefly describe the metabolism of glucose, fatty acids, and amino acids during the fasted (basal) state. Be specific by including the liver, brain, RBC, muscle adipose tissue, and kidney?

Answer 1

The liver is a key metabolic organ which governs body energy metabolism. It acts as a hub to metabolically connect to various tissues, including skeletal muscle and adipose tissue. Food is digested in the gastrointestinal (GI) tract, and glucose, fatty acids, and amino acids are absorbed into the bloodstream and transported to the liver through the portal vein circulation system. In the postprandial state, glucose is condensed into glycogen and/or converted into fatty acids or amino acids in the liver. In hepatocytes, free fatty acids are esterified with glycerol-3-phosphate to generate triacylglycerol (TAG). TAG is stored in lipid droplets in hepatocytes or secreted into the circulation as very low-density lipoprotein (VLDL) particles. Amino acids are metabolized to provide energy or used to synthesize proteins, glucose, and/or other bioactive molecules. In the fasted state or during exercise, fuel substrates (e.g. glucose and TAG) are released from the liver into the circulation and metabolized by muscle, adipose tissue, and other extrahepatic tissues. Adipose tissue produces and releases nonesterified fatty acids (NEFAs) and glycerol via lipolysis. Muscle breaks down glycogen and proteins and releases lactate and alanine. Alanine, lactate, and glycerol are delivered to the liver and used as precursors to synthesize glucose (gluconeogenesis). NEFAs are oxidized in hepatic mitochondria through fatty acid β oxidation and generate ketone bodies (ketogenesis). Liver-generated glucose and ketone bodies provide essential metabolic fuels for extrahepatic tissues during starvation and exercise.

Liver energy metabolism is tightly controlled. Multiple nutrient, hormonal, and neuronal signals have been identified to regulate glucose, lipid, and amino acid metabolism in the liver. Dysfunction of liver signaling and metabolism causes or predisposes to nonalcoholic fatty liver disease (NAFLD) and/or type 2 diabetes.

1. LIVER GLUCOSE METABOLISM

Hepatocytes are the main cell type in the liver (~80%). Blood glucose enters hepatocytes via GLUT2, a plasma membrane glucose transporter. Hepatocyte-specific deletion of GLUT2blocks hepatocyte glucose uptake (231). GLUT2 also mediates glucose release from the liver; however, deletion of GLUT2 does not affect hepatic glucose production in the fasted state (231), suggesting that glucose is able be released from hepatocytes through additional transporters (e.g. GLUT1) or by other mechanisms. Glucose is phosphorylated by glucokinase in hepatocytes to generate glucose 6-phosphate (G6P), leading to a reduction in intracellular glucose concentrations which further increases glucose uptake (Fig. 1). Moreover, G6P is unable to be transported by glucose transporters, so it is retained within hepatocytes. In the fed state, G6P acts as a precursor for glycogen synthesis (Fig. 1). It is also metabolized to generate pyruvate through glycolysis. Pyruvate is channeled into the mitochondria and completely oxidized to generate ATP through the tricarboxylic acid (TCA) cycle (Fig. 1) and oxidative phosphorylation. Alternatively, pyruvate is used to synthesize fatty acids through lipogenesis (Fig. 3). G6P is also metabolized via the pentose phosphate pathway to generate NADPH (Fig. 1). NADPH is required for lipogenesis and biosynthesis of other bioactive molecules. In the fasted state, G6P is transported into the endoplasmic reticulum (ER) and dephosphorylated by glucose-6-phosphatase (G6Pase) to release glucose.

2. LIVER FATTY ACID METABOLISM

When carbohydrates are abundant, the liver not only utilizes glucose as the main metabolic fuel but also converts glucose into fatty acids. Hepatocytes also obtain fatty acids from the bloodstream, which are released from adipose tissue or absorbed from food digestion in the GI. Fatty acids are esterified with glycerol 3-phosphate to generate TAG (Fig. 3) or with cholesterol to produce cholesterol esters. TAG and cholesterol esters are either stored in lipid droplets within hepatocytes or secreted into the circulation as VLDL particles. Fatty acids are also incorporated into phospholipids, which are an essential component of cell membranes, and the surface layer of lipid droplets, VLDL, and bile particles. In the fasted state, fatty acids are oxidized mainly in the mitochondria to generate energy supply as well as ketone bodies.

The liver has long been recognized to be an essential metabolic organ. When carbohydrates are abundant during the postprandial phase, the liver converts glucose into glycogen and lipids, which provide metabolic fuels during fasting. In the fasted state, the liver produces and secretes glucose through both glycogenolysis and gluconeogenesis. The liver also converts fatty acids into ketone bodies which provide additional metabolic fuels for extrahepatic tissues during fasting. The metabolic switch between the fasted and fed states in the liver is tightly controlled by neuronal and hormonal systems. Insulin suppresses glucose production and ketogenesis and stimulates glycolysis and lipogenesis in the liver. Insulin resistance is not only a hallmark of type 2 diabetes but also promotes type 2 diabetes progression in obesity. Glucagon counteracts insulin action, and defects in glucagon signaling lead to hypoglycemia. Hepatic energy metabolism is largely controlled at the genomic levels by numerous transcription factors and coregulators. The activity of these nuclear proteins is regulated by insulin, glucagon and other metabolic hormones, which dynamically regulates gluconeogenesis, β oxidation, and lipogenesis in the liver in order to meet a systemic metabolic demand. Dysregulation of these transcription factors and coregulators contributes to NAFLD in obesity. Moreover, systemic insulin resistance promotes NAFLD, and hepatocyte lipid accumulation further impairs insulin action, thus activating the insulin resistance-lipotoxicity vicious cycle which drives NAFLD and/or type 2 diabetes progression.