Nutrient-sensing mechanisms and pathways

Abstract

The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases.

Figure 1. Lipid Sensing Mechanism

A. Fatty Acid (FA) detection mechanisms by GPR40 and 120 (left) and CD36 (right). These GPR family members are expressed in several cell types including entero-endocrine cells, taste buds and white adipocytes. In the enteroendocrine cells, binding to FAs occurs in the luminal side, and the signal is transduced via G protein, leading to the release of incretins into the circulation. In taste buds, they trigger the release of neurotransmitters; in white adipocytes, activation of GPR120 indirectly promotes glucose uptake. Binding of CD36 to free FAs in the oral taste buds triggers Ca⁺⁺ release and neurotransmission; in enterocytes, it directly promotes FA uptake. B. Cholesterol sensing by SCAP. In the presence of cholesterol, the SCAP/SREBP complex binds the INSIG proteins at the endoplasmic reticulum (ER) membrane and remains anchored in the ER. When cholesterol is absent and SCAP/SREBP do not bind INSIG, the complex traffics to the Golgi where the cytoplasmic tail of SREBP gets released by proteolytic cleavage, and triggers a cholesterol synthesis transcriptional program at the nucleus, including the synthesis of HMG-CoA reductase (HMGCR). C. The enzyme HMGCR catalyzes a rate-limiting step in cholesterol synthesis, and is synthesized when cholesterol levels are low. HMGCR is embedded in the ER membrane and also has cytoplasmic domains, which include its catalytic activity. In the presence of abundant intermediate species in the cholesterol biosynthetic pathway, HMGCR interacts with the INSIG proteins, constitutively bound to an ubiquitination complex. This leads to HMGCR ubiquitination and degradation and halts the synthesis of cholesterol in a rapid regulatory mechanism, key to the anticipation of an imminent increase in cholesterol levels.

Figure 2. Amino acid Sensing Mechanisms

A. GCN2 detects insufficiencies of cellular amino acids (AAs). During low levels of any AA, its cognate aaRS fails to load the transfer RNA (tRNA), which is then detected by GCN2 kinase, halting translation initiation. B. mTORC1 is activated downstream of elevated intracellular AAs via its recruitment to the outer lysosomal surface through a Rag GTPase-mediated mechanism. Increases in intra-lysosomal levels of AAs control Rag GTPase function, which recruits mTORC1 to the outer lysosomal membrane, an essential step in its activation. The identities of the sensor for AAs remain unidentified, and several non-mutually exclusive possibilities exist: a) an intra-lysosomal sensor that transduces the signal through the membrane; b) a lysosomal transmembrane sensor that both detects and transduces the signal; and c) and a cytoplasmic sensor that operates downstream of AA export from the lysosome. C. Extra-organismal AA sensing by oral taste receptors. The heterodimeric receptor T1R1+T1R3 binds AAs at high concentrations only, and triggers a signal transduction cascade via G-protein. In the intestinal epithelium, it also leads to the localization of GLUT2 to the apical membrane, facilitating glucose import.

Figure 3. Glucose Sensing Mechanisms

A. Glucose sensing by the GLUT2 transporter. Due to low affinity, this transporter actively imports glucose only during high glycaemic states (right). Due to its bidirectional properties, it can also export glucose from hepatocytes into the circulation under hypoglycaemic states if hepatic gluconeogenesis and glycogen breakdown raise the intrahepatic glucose levels (left) B. Intracellular glucose sensing by glucokinase (GCK) in hepatic and pancreatic cells. GCK has low affinity for glucose, and shunts glucose-6-phosphate into either glycolysis or glycogen synthesis only when glucose is abundant. C. Mechanism of insulin release downstream of glucose sensing in pancreatic beta-cells. A multi-step process that relies on glucose phosphorylation by GCK, subsequent ATP production, and ATP-mediated blockade of K⁺ channels. This leads to a Ca⁺⁺ influx that facilitates insulin release from vesicles into the bloodstream. D. Extra-organismal glucose sensing by oral taste receptors. Dimeric receptors T1R2+T1R3 bind glucose, sucrose, fructose and artificial sweeteners at high concentration only, and trigger a signal transduction cascade via G-protein.

Figure 4. Nutrients and Autophagy

Autophagy serves as an internal source of stored nutrients under conditions of nutrient limitation. Two main regulatory inputs for autophagy are AMPK and mTORC1. Autophagy initiation can be promoted by the activation of ULK1 via AMPK-dependent phosphorylation during low ATP:AMP ratio. mTORC1 is activated by growth factors at the outer lysosomal surface if cellular AAs and glucose have recruited mTORC1 via the action of the Rag GTPases. Once activated, mTORC1 inhibits ULK1 and Atg13 by phosphorylation. Hence, low nutrients promote autophagy by the inhibition of mTORC1. Autophagy starts with the engulfment of cellular constituents: glycogen, lipids from lipid droplets, soluble proteins, ribosomes or organelles in a double membrane structure that then fuses with lysosomes, where the enzymatic breakdown occurs. The products of autophagy, basic nutrients (sugars, lipids, amino acid, and nucleosides), are then exported into the cytoplasm, where may be used as a source of energy, or re-used for anabolism.