Le principali vie del metabolismo energetico nei mammiferi proteine aminoacidi urea glicogeno glucosio 6-P triacilgliceroli acidi grassi piruvato acetilCoA Corpi chetonici ossalacetato Degradazione degli aminoacidi sintesi degli aminoacidi sintesi degli acidi grassi  -ossidazione sintesi del glicogeno Degradazione del glicogeno gluconeogenesi glicolisi Ciclo dell’acido citrico Fosforilazione ossidativa ATP ATP ATP ATP

Correlazioni metaboliche tra cervello, tessuto adiposo, muscolo e fegato Corpi chetonici glucosio H 2 O + CO 2 Corpi chetonici AcetilCoA Acidi grassi triacilgliceroli glicerolo lattato piruvato glucosio glicogeno urea aminoacidi proteine Acidi grassi glicerolo glucosio triacilgliceroli Acidi grassi Corpi chetonici aminoacidi proteine lattato piruvato glucosio glicogeno H 2 O + CO 2 CO 2 + H 2 O Alanina + glutamina

Vie di collegamento metabolico tra vari organi: ciclo di Cori lattato glucosio ATP + GTP ADP + GDP + P i GLUCONEOGENESI glucosio glicogeno GLICOGENOLISI E GLICOLISI ADP + P i ATP lattato SANGUE

Vie di collegamento metabolico tra vari organi: ciclo dell’alanina piruvato glucosio GLUCONEOGENESI glucosio piruvato  -aminoacido alanina alanina NH 3 urea  -chetoacido glicogeno TRANSAMINAZIONE SANGUE

0 12-24 Hours of starvation Relative change plasma insulin plasma glucagon liver glycogen blood glucose plasma free fatty acids blood ketone bodies Relative changes in metabolic parameters during the onset of starvation

estimated consumption in humans: 8-10 g/h ( ~ 50% by the brain) pool of circulating glucose: 5 g production in the overnight fasted state : ~ 6 5% from liver glycogen breakdown and 35% from splanchnic gluconeogenesis (18% from aminoacids, 14% from lactate, 2% from glycerol and 1% from piruvate) in prolonged fasting (> 60 h) the contribution of kidneys to glucose output raises to 20-25% Glucose in numbers

estimated consumption in humans: 8-10 g/h ( ~ 50% by the brain)

pool of circulating glucose: 5 g

production in the overnight fasted state : ~ 6 5% from liver glycogen breakdown and 35% from splanchnic gluconeogenesis (18% from aminoacids, 14% from lactate, 2% from glycerol and 1% from piruvate)

in prolonged fasting (> 60 h) the contribution of kidneys to glucose output raises to 20-25%

All living cells must continously maintain a high, non equilibrium ratio of ATP to ADP Because of the adenylate kinase reaction (2ADP  ATP + P i ) AMP raises whenever the ATP/ADP ratio falls High cellular ratio of AMP/ATP is a signal that the energy status of the cell is compromized AMP-kinase is switched on by cellular stresses that interfere with ATP production (hypoxia, glucose deprivation or ischemia) or by stresses that increase ATP consumption (muscle contraction) Key sensors of cellular energy status and nutrient availability: the AMP/AMP-kinase system

All living cells must continously maintain a high, non equilibrium ratio of ATP to ADP

Because of the adenylate kinase reaction (2ADP  ATP + P i ) AMP raises whenever the ATP/ADP ratio falls

High cellular ratio of AMP/ATP is a signal that the energy status of the cell is compromized

AMP-kinase is switched on by cellular stresses that interfere with ATP production (hypoxia, glucose deprivation or ischemia) or by stresses that increase ATP consumption (muscle contraction)

Key sensors of cellular energy status and nutrient availability: malonyl-CoA malonyl-CoA is a biochemical sensor that switches substrate oxidation from fatty acids to glucose (inhibition of CPT1  reduced lipid oxidation  lipid storage into triglycerides) Malonyl-CoA is produced by acetyl-CoA carboxylase, ACC (two isoforms). ACC1 is cytosolic, expressed in lipogenic cell types and involved in fatty acid synthesis. ACC2 is anchored in the mitochondrial membrane and is expressed in cell types where malonyl-CoA governs the entry of fatty acids into mitochondria (i.e. skeletal muscle) Both ACC1 and ACC2 are similarly regulated: by citrate , feed-forward allosteric activator; by AMP-K that phosphorylates and inactivates ACC Skeletal muscle also expresses malonyl-CoA decarboxylase (MCD) whose sole function is to decarboxylate malonyl-CoA to acetyl-Co-A

malonyl-CoA is a biochemical sensor that switches substrate oxidation from fatty acids to glucose (inhibition of CPT1  reduced lipid oxidation  lipid storage into triglycerides)

Malonyl-CoA is produced by acetyl-CoA carboxylase, ACC (two isoforms). ACC1 is cytosolic, expressed in lipogenic cell types and involved in fatty acid synthesis. ACC2 is anchored in the mitochondrial membrane and is expressed in cell types where malonyl-CoA governs the entry of fatty acids into mitochondria (i.e. skeletal muscle)

Both ACC1 and ACC2 are similarly regulated: by citrate , feed-forward allosteric activator; by AMP-K that phosphorylates and inactivates ACC

Skeletal muscle also expresses malonyl-CoA decarboxylase (MCD) whose sole function is to decarboxylate malonyl-CoA to acetyl-Co-A

Key sensors of cellular energy status and nutrient availability: glucose glucose is primarily used in the synthesis of glycogen and glycolysis but a small fraction (1-3%) enters the hexosamine biosynthesis pathway  UDP-N-actylglucosamine (protein glycosylation)  nutrient-dependent post-transcriptional modification of enzymes, transporters, etc.

glucose is primarily used in the synthesis of glycogen and glycolysis but a small fraction (1-3%) enters the hexosamine biosynthesis pathway  UDP-N-actylglucosamine (protein glycosylation)

 nutrient-dependent post-transcriptional modification of enzymes, transporters, etc.

Levels of amino acids in anterior piriform cortex (APC) 20 min after introduction of Normal diet Diet deprived of indispensable amino acids Nearly half of the AAs present in protein cannot be synthesized or stored in metazoans because the genes for their synthesis were lost early in evolution; these are the essential or dietary indispensable amino acids (IAAs). 1. Maintenance of indispensable amino acid (IAA) homeostasis is essential for protein synthesis and survival, requiring dietary selection in omnivores (animals adopt behavioral strategies some of which are adaptive in the longer term and associated with learning). 2. For appropriate dietary selection, sensing the depletion of an IAA is a crucial first step. 3. The brain area housing the IAA sensor is the anterior piriform cortex (APC). 4. The mechanism of IAA sensing in the APC is the conserved general amino acid control pathway. 5. The four steps of the sensory mechanism are decreased IAA, increased deacylated tRNA, activation of GC nonderepressing kinase 2, and phosphorylation of eukaryotic initiation factor 2α, which binds to eIF2B and blocks initiation of translation. 6. The APC is highly excitable and has oscillatory activity coordinated with respiration. 7. Several signal transduction systems may be involved in potentiating the output cells of the APC. The aminoacid sensing system

Controllo ormonale del metabolismo: insulina traslocazione dei GLUT4 (muscolo e tessuto adiposo) utilizzo del glucosio introdotto con la dieta (~50% glicolisi, ~ 30-40% convertito in grassi, ~10% convertito in glicogeno) inibizione gluconeogenesi effetto ipoglicemizzante azione lipogenica e inibizione della lipolisi effetto anabolico (rallentamento della degradazione delle proteine) stimolazione della proliferazione (effetto mitogeno) legame e attivazione del recettore (tirosin chinasi)  attivazione di una cascata di fosforilazione di proteine segnale  1) traslocazione di proteine (es. GLUT4); 2) modulazione dell’attività enzimatica mediante defosforilazione (es. glicogeno sintasi, fosforilasi chinasi, piruvato DH, piruvato chinasi, PFK-2, fruttosio-2,6-bisfosfato fosfatasi, acetil-CoA carbossilasi, HMG-CoA reduttasi, trigliceride lipasi); 3) regolazione della trascrizione genica (  glucochinasi, GAPDH, piruvato chinasi, PEPCK, glucagone, etc.) 4) stabilità e traduzione mRNA EFFETTI METABOLICI MECCANISMO D’AZIONE

traslocazione dei GLUT4 (muscolo e tessuto adiposo)

utilizzo del glucosio introdotto con la dieta (~50% glicolisi, ~ 30-40% convertito in grassi, ~10% convertito in glicogeno)

inibizione gluconeogenesi

effetto ipoglicemizzante

azione lipogenica e inibizione della lipolisi

effetto anabolico (rallentamento della degradazione delle proteine)

stimolazione della proliferazione (effetto mitogeno)

Captazione e metabolismo del glucosio (glicolisi accoppiata a ciclo degli acidi tricarbossilici) secrezione dell'insulina (glucosio-mediata)  ATP/ADP Secrezione dell’insulina da parte delle cellule  del pancreas Cell. 2001, 105(6):745-55 Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes UCP2 Mitochondrial proton leak  ATP/ADP Reduced insulin secretion UCP2 is markedly upregulated in islets of ob/ob mice

Insulin signaling: phosphorylation state of IRS1 p-S S-p p-S p-S p-Y p-Y Y-p Y-p IRS-1 Y-p Y-p PI3K IR ERKs JNKs PKC mTOR S6K PKB IRS-1 Y-p IRS-1 Y-p Y-p Y-p REDUCED IRS1 FUNCTIONS NEGATIVE FEEDBACK LOOP ENHANCED IRS1 FUNCTIONS POSITIVE FEEDBACK LOOP

Impaired insulin signaling Hyperactivation of mTOR by amino acids, Akt, or hyperinsulinemia results in serine phosphorylation of IRS-1 by p70S6 kinase, with a subsequent decrease in the strength of the IRS-1/PI 3-kinase signaling. In addition, serine phosphorylation of IRS-1 can be promoted by JNK, PKC, IKKß, and TNF  . Insulin receptor hyperinsulinemia IRS-1 IRS-1 is phosphorylated by the tyrosine kinase of the insulin receptor in response to insulin binding. PI 3-kinase Protein/lipid kinase, PI 3-kinase, binds to the specific MYMX motifs of IRS-1, containing phosphorylated tyrosine residues. Akt mTOR p70S6 kinase PI 3-kinase is then activated and initiates a downstream cascade of events leading to the phosphorylation and activation of Akt, mTOR, and p70S6 kinase. Activation of Akt appears to be important for glucose transport, while activation of mTOR and p70S6 kinase participates in the process of protein synthesis. Serine P JNK, PKC, IKKß, and TNF  Amino acids

Impaired insulin signaling: PI3 kinase PI3 kinase is a heterodimer consisting of a catalytic (p110) and a regulatory subunit. The most abundant isoform of the regulatory subunit is p85 Increased expression of p85 monomer competes with and displaces the p85-p110 heterodimer from the IRS-1 binding sites. The resultant decrease in association of p110 with IRS-1 diminishes PI 3-kinase activity and the downstream effects of this kinase Steroids, growth hormone (GH), human placental growth hormone (hPGH), short-term overfeeding, obesity, and type 2 diabetes (T2DM) have been shown to increase p85 expression Insulin receptor IRS-1 Akt p85 p110 GH, hPGH, steroids, overfeeding, obesity, T2DM p85 p85 p85

PI3 kinase is a heterodimer consisting of a catalytic (p110) and a regulatory subunit. The most abundant isoform of the regulatory subunit is p85

Increased expression of p85 monomer competes with and displaces the p85-p110 heterodimer from the IRS-1 binding sites. The resultant decrease in association of p110 with IRS-1 diminishes PI 3-kinase activity and the downstream effects of this kinase

Steroids, growth hormone (GH), human placental growth hormone (hPGH), short-term overfeeding, obesity, and type 2 diabetes (T2DM) have been shown to increase p85 expression

An apple may be good for you, but an apple figure with excess weight in the middle, isn't. What is the metabolic syndrome? The metabolic syndrome is characterized by a group of metabolic risk factors in one person. They include: Central obesity (excessive fat tissue in and around the abdomen) Atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls) Raised blood pressure (130/85 mmHg or higher) Insulin resistance or glucose intolerance (the body can’t properly use insulin or blood sugar) Prothrombotic state Proinflammatory state =

What is the metabolic syndrome?

The metabolic syndrome is characterized by a group of metabolic risk factors in one person. They include:

Central obesity (excessive fat tissue in and around the abdomen)

Atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls)

Raised blood pressure (130/85 mmHg or higher)

Insulin resistance or glucose intolerance (the body can’t properly use insulin or blood sugar)

Prothrombotic state

Proinflammatory state

WHO HAS THE METABOLIC SYNDROME The metabolic syndrome has become increasingly common in the United States. It’s estimated that about 20-25% of US adults have it. The syndrome is closely associated with a generalized metabolic disorder called insulin resistance , in which the body can’t use insulin efficiently. This is why the metabolic syndrome is also called the insulin resistance syndrome. Some people are genetically predisposed to insulin resistance. Acquired factors , such as excess body fat and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have central obesity. The biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors aren’t fully understood and appear to be complex.

The metabolic syndrome has become increasingly common in the United States. It’s estimated that about 20-25% of US adults have it.

The syndrome is closely associated with a generalized metabolic disorder called insulin resistance , in which the body can’t use insulin efficiently. This is why the metabolic syndrome is also called the insulin resistance syndrome.

Some people are genetically predisposed to insulin resistance. Acquired factors , such as excess body fat and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have central obesity. The biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors aren’t fully understood and appear to be complex.

Liporegulation, lipid partitioning, obesity Adiponectina (ACRP30) leptina Ormone peptidico (i recettori sono espressi prevalentemente a livello ipotalamico) Prodotto del gene ob Espressa nelle cellule del tesssuto adiposo Regola negativamente la quantità di tessuto adiposo: aumenta quando si acquista peso e diminuisce quando si perde peso Ha effetti sul metabolismo energetico (attiva AMP-K nel muscolo scheletrico quindi l’ossidazione degli acidi grassi) Obesità spesso si correla a ridotta sensibilità all’azione della leptina TNF  Fattore prodotto e secreto da adipociti ruolo nella sensibilità all’insulina (nel muscolo e nel fegato) Attiva AMP-K in fegato e muscolo scheletrico dove promuove ossidazione di acidi grassi e glucosio e inibisce la gluconeogenesi i livelli circolanti diminuiscono in soggetti obesi e con diabete di tipo II Citochina proinfiammatoria prodotta da numerosi tipi cellulari (anche adipociti) induce insulino-resistenza

Ormone peptidico (i recettori sono espressi prevalentemente a livello ipotalamico)

Prodotto del gene ob

Espressa nelle cellule del tesssuto adiposo

Regola negativamente la quantità di tessuto adiposo: aumenta quando si acquista peso e diminuisce quando si perde peso

Ha effetti sul metabolismo energetico (attiva AMP-K nel muscolo scheletrico quindi l’ossidazione degli acidi grassi)

Obesità spesso si correla a ridotta sensibilità all’azione della leptina

Fattore prodotto e secreto da adipociti

ruolo nella sensibilità all’insulina (nel muscolo e nel fegato)

Attiva AMP-K in fegato e muscolo scheletrico dove promuove ossidazione di acidi grassi e glucosio e inibisce la gluconeogenesi

i livelli circolanti diminuiscono in soggetti obesi e con diabete di tipo II

Citochina proinfiammatoria prodotta da numerosi tipi cellulari (anche adipociti)

induce insulino-resistenza

When normal healthy individuals are in caloric balance, their liporegulatory system is at rest (leptin levels are low) Liporegulation and lipid partitioning (IA)

Liporegulation and lipid partitioning (IB) When normal healthy individuals chronically consume more calories than are needed to meet the caloric expenditure, adipocytes will expand and leptin levels will rise in proportion to the degree of lipid overload. By promoting fatty acid oxidation and deterring lipogenesis the hyperleptinemia maintains the lean tissue content of lipids at a near-normal level.

Lipid partitioning in diet-induced obesity In visceral obesity the circulating level of leptin although higher than normal may not be high enough to provide effective antisteatosis Resistance to leptin in its target tissues Lipid storage in lean tissues leads to dysfunction (lipotoxicity)

Generalized obesity Hyperleptinemia, better ability to limit ectopic lipid accumulation

High-fructose diets have been shown to induce insulin resistance, weight gain, hyperlipidemia, and hypertension in several animal models. In human studies, fructose consumption was associated with the development of hepatic and adipose tissue insulin resistance and dyslipidemia due to its ability to induce hepatic de novo lipogenesis dihydroxyacetone-P glyceraldheyde-3P piruvate lactate acetyl-CoA ALDOLASE B fructose FRUCTOKINASE Km < 0.5 mM fructose-1-P glyceraldehyde glycerol TRIOKINASE Dihydroxy acetone-P Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev. 2007 65:S13-23 Fatty acids Glycerol-3P Fructose and insulin resistance

SREBPs: caratteristiche e regolazione SREBP-1a: codificata dallo stesso gene che codifica per SREBP-1c. Il gene presenta due siti di inizio della trascrizione e due esoni 1. L’esone 1a codifica per un segmento più lungo con una maggiore capacità di transattivazione. SREBP-1c: effetto sulla trascrizione più ristretto rispetto a SREBP-1a. SREBP-2: codificata da un gene distinto da quello che codifica per SREBP-1a/c. REGOLAZIONE DELL’ATTIVITA’ DI SREBP a livello della trascrizione (insulina, LXR inducono SREBP-1c) a livello post-traduzionale (proteolisi)

REGOLAZIONE DELL’ATTIVITA’ DI SREBP

a livello della trascrizione

(insulina, LXR inducono SREBP-1c)

a livello post-traduzionale (proteolisi)

G6PD , glucose-6-phosphate dehydrogenase PGDH 6-phosphogluconate dehydrogenase GPAT glycerol-3-phosphate acyltransferase. Genes regulated by SREBPs In vivo, SREBP-2 preferentially activates genes of cholesterol metabolism In vivo, SREBP-1c preferentially activates genes of fatty acid and triglyceride metabolism DHCR 7-dehydrocholesterol reductase FPP farnesyl diphosphate GPP geranylgeranyl pyrophosphate synthase CYP51 lanosterol 14α-demethylase.

PPARs: caratteristiche e funzioni Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. These receptors stimulate transcription after activation by their cognate ligand and binding to the promoter of target genes. Several PPAR subtypes have been described and named PPARa, PPARb/d, PPARg,. The different forms are expressed in tissue-specific patterns and exhibit distinct functions: PPAR  is abundantly found in liver, kidney, heart, and muscle (fatty acid catabolism and modulation of the inflammatory response); PPAR  is localized in fat, large intestine, and macrophages (adipocytic differentiation, monocytic differentiation and cell cycle withdrawal); PPAR  /  are widely expressed (embryo implantation, cell proliferation and apoptosis)

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level.

These receptors stimulate transcription after activation by their cognate ligand and binding to the promoter of target genes.

Several PPAR subtypes have been described and named PPARa, PPARb/d, PPARg,. The different forms are expressed in tissue-specific patterns and exhibit distinct functions:

PPAR  is abundantly found in liver, kidney, heart, and muscle (fatty acid catabolism and modulation of the inflammatory response);

PPAR  is localized in fat, large intestine, and macrophages (adipocytic differentiation, monocytic differentiation and cell cycle withdrawal);

PPAR  /  are widely expressed (embryo implantation, cell proliferation and apoptosis)

PPAR  : effetti metabolici PPARa ligands Transcription activation Lipid binding protein Microsomal w-oxidation Mitochondrial b-oxidation peroxisomal  -oxidation Dicarboxylic acids // oxidation oxidation very long chain fatty acids, branched chain fatty acids, pristanic acid

PPAR  agonists  glucose uptake  lipid uptake and storage  energy expenditure regulate secreted factors GLUT4 CD36, FATP, aP2, ACS, etc. glycerol kinase, UCP2, UCP3  ACRP30,  TNF  , leptin  insulin sensitivity: ACRP30  FFAs  insulin resistance: TNF   insulin sensitivity: ACRP30  gluconeogenesis  PEPCK  glucose oxidation:  PDK4  lipid uptake and storage  energy expenditure CD36, aP2 UCP2 PPAR  : effetti metabolici

LXRs: caratteristiche e funzioni Role of LXRs Cholesterol homeostasis Glucose metabolism Two genes encode highly conserved isoforms. LXR  : expressed in tissue specific manner LXR  : ubiquitously expressed Upregulated by PPARg. Target genes: CYP7A1 (bile acid synthesis), ABC transporters (cholesterol efflux), ApoE (cholesterol acceptor), CETP (lipoprotein remodeling), LPL , SREBP1-c (fatty acid metabolism), LXR  .

Mechanisms underlying LXR-mediated regulation of gene transcription LXRE Transcription factor RXR LXR Oxysterols glucose + Responsive element Target gene + TF TF TF TF SREBP-1c Fatty acid synthase LXRE Target gene RXR LXR Oxysterols glucose + ABCA1 apoE

LXRs: effetto sull’omeostasi del colesterolo cholesterol ABCs apoE HDL cholesterol Bile acids CYP7A1 - BLOOD ABCs macrophage INTESTINAL LUMEN cholesterol Bile acids DIET ABCs cholesterol EFFLUX AND TRANSPORT CATABOLISM EXCRETION ABSORPTION

LXR  acts as insulin-sensitizer in liver and adipose tissue where it represses gluconeogenesis and promotes glucose uptake and storage induction of GK and repression of gluconeogenetic genes in liver PPAR  stimulates hepatic gluconeogenesis to meet the metabolic needs of the body during fasting by inducing conversion of glycerol that is produced in adipose tissue through lypolisis, into glucose in the liver. Up-regulation of hepatic glycerol 3P dehydrogenase, glycerol kinase and glycerol transporters PPAR  mediates insulin action in insulin-sensitive tissues promoting glucose utilization in skeletal muscle, repressing gluconeogenesis in the liver, and contributing to inter-organ cross-talk ROLE OF FATTY ACID AND OXYSTEROL SENSING RECEPTORS IN THE CONTROL OF METABOLIC PATHWAYS (I) GLUCOSE METABOLISM

LXR  acts as insulin-sensitizer in liver and adipose tissue where it represses gluconeogenesis and promotes glucose uptake and storage

induction of GK and repression of gluconeogenetic genes in liver

PPAR  stimulates hepatic gluconeogenesis to meet the metabolic needs of the body during fasting by inducing conversion of glycerol that is produced in adipose tissue through lypolisis, into glucose in the liver.

Up-regulation of hepatic glycerol 3P dehydrogenase, glycerol kinase and glycerol transporters

PPAR  mediates insulin action in insulin-sensitive tissues promoting glucose utilization in skeletal muscle, repressing gluconeogenesis in the liver, and contributing to inter-organ cross-talk

PPAR  is a master regulator of fatty acid utilization in the liver during the fasted state Induction of genes involved in fatty acids oxidation. PPAR  inactivation leads to hypoketonemia, hypothermia, elevated free fatty acids, hypoglycemia the regulatory circuit involving LXR  and SREBP-1c is responsible for the lipogenic response of the liver and adipose tissue to insulin Induction of FAS and other genes involved in fatty acid synthesis. Insulin regulates Srebp-1c transcription through an LXRE PPAR  and LXR  are required for adipocyte differentiation and lipogenic activity of adipose tissue PPAR  /  is mainly involved in fatty acid utilization and energy dissipation in adipose tissue and skeletal muscle (control of adiposity and adaptation of fibers in skeletal muscle to endurance exercise) ROLE OF FATTY ACID AND OXYSTEROL SENSING RECEPTORS IN THE CONTROL OF METABOLIC PATHWAYS (II) FATTY ACID METABOLISM

PPAR  is a master regulator of fatty acid utilization in the liver during the fasted state

Induction of genes involved in fatty acids oxidation. PPAR  inactivation leads to hypoketonemia, hypothermia, elevated free fatty acids, hypoglycemia

the regulatory circuit involving LXR  and SREBP-1c is responsible for the lipogenic response of the liver and adipose tissue to insulin

Induction of FAS and other genes involved in fatty acid synthesis. Insulin regulates Srebp-1c transcription through an LXRE

PPAR  and LXR  are required for adipocyte differentiation and lipogenic activity of adipose tissue

PPAR  /  is mainly involved in fatty acid utilization and energy dissipation in adipose tissue and skeletal muscle (control of adiposity and adaptation of fibers in skeletal muscle to endurance exercise)

LXRs participate to the physiological repression of cholesterol synthesis under normal conditions Genetic inactivation of LXRs leads to derepressed cholesterol synthesis LXRs positively regulate the transport of cholesterol from extrahepatic tissues to the liver acting on different target genes LXRs are sensors of dietary cholesterol and facilitate elimination of excess cholesterol through bile acids in rodents activation of PPAR  in the liver may lead to decreased bile acid synthesis and secretion into bile ROLE OF FATTY ACID AND OXYSTEROL SENSING RECEPTORS IN THE CONTROL OF METABOLIC PATHWAYS (III) CHOLESTEROL METABOLISM

LXRs participate to the physiological repression of cholesterol synthesis under normal conditions

Genetic inactivation of LXRs leads to derepressed cholesterol synthesis

LXRs positively regulate the transport of cholesterol from extrahepatic tissues to the liver acting on different target genes

LXRs are sensors of dietary cholesterol and facilitate elimination of excess cholesterol through bile acids in rodents

activation of PPAR  in the liver may lead to decreased bile acid synthesis and secretion into bile