**1. Introduction**

234 Dyslipidemia - From Prevention to Treatment

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77.

Control of energy metabolism is crucial for optimal functioning of organs and tissues. Amongst all nutrients, glucose is the principal energy source for most cells and, therefore, minimum blood glucose levels must be guaranteed. Alterations in glycaemia can lead to hyperglycaemic states (producing protein glycosylation and toxicity in glucose-sensitive cells) or hypoglycaemic states (that can affect brain function), both harmful. Therefore, mechanisms must exist to keep glycaemia in a narrow physiological range (4-8 mM) independently of the nutritional state. To achieve control of blood glucose levels, our body has a complex, interorgan signaling system using nutrients (glucose, lipids, amino acids), hormones (insulin, glucagon, ghrelin, etc.) and the autonomic nervous system. In response to these signals, organs and tissues (mainly intestine, endocrine pancreas, liver, skeletal muscle, adipose tissue, brain and adrenal glands) adapt their function to energetic requirements.

The liver plays a pivotal role in the maintenance of glucose homeostasis by continuously adapting its metabolism to energetic needs. In the fed state, when blood glucose levels are high and there is insulin, liver takes-up part glucose to replenish glycogen stores. Besides, when glucose stores are full, the liver has the capacity to synthesize lipids *de novo* from glucose for-long term energy storage. Lipids are packaged in very low-density lipoprotein (VLDL) particles and then transported to the adipose tissue. Conversely during starvation, when glycaemia falls and glucagon increases, the liver produces glucose to maintain circulating glucose levels by breaking down glycogen stores or by synthesizing glucose de novo through gluconeogenesis. Gluconeogenesis, as an energy-consuming pathway, is linked to β-oxidation of fatty acids (fuel supplier pathway).

From this introduction on the regulation of glucose homeostasis, one can appreciate the close relation that exists between carbohydrate metabolism and lipid metabolism in the liver. Therefore, alterations in hepatic carbohydrate metabolic pathways may directly affect hepatic and/or blood lipid levels. Particularly, this chapter will focus on evaluating the incidence of glucokinase (GK) –the first enzyme of the glycolytic pathway in the liveron lipidemia and on hepatic lipid content. But first, an introductory overview of the physiology behind the first-pass metabolism of dietary glucose in the liver will be presented.

Liver Glucokinase and Lipid Metabolism 237

NADP NADPH

Ribulose-5P

Xylulose-5P

*6-PGDH*

*epimerase*

NADP

NADPH

6-Phosphogluconate

LIPID DROPLETS

*G6P-DH*

Glucose

*GLUT-2*

Glucose

Glucose-6P *GK*

Fructose-6P

Fructose-2,6-bP Fructose-1,6-bP *PFK2*

Phosphoenolpyruvate

Pyruvate Acetyl-CoA *PDH*

*Krebs cycle*

*Mitochondrion*

Citrate

Citrate

glucokinase; PFK-2, 6, phosphofructo-2-kinase/fructose-2,6-bisphosphatase; L-PK, liverpyruvate kinase). On the other hand, glucose is oxidized through pentose phosphate pathway to obtain NADPH (G6P-DH means glucose-6-phosphate dehydrogenase; 6-PGDH, 6-phosphogluconate dehydrogenase). Pyruvate enters the mitochondrion to obtain citrate (PDH means, pyruvate dehydrogenase; MDH, malate dehydrogenase and EM, malic enzyme). De novo synthesis of fatty acids starts with citrate (ATP-CL means ATP citrate lyase; ACC, acetyl-CoA carboxylase) and after suffering elongation and desaturation reactions (ELOVL6 means elongase that catalyzes the conversion of palmitate to stearate; SCD-1, stearoyl-coenzyme A desaturase), fatty acids are converted to triglyceride (TAG) (GPAT means glycerol-3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase). Triglyceride can be stored in the liver but are mostly packaged into VLDL (very low-density lipoprotein) and secreted to bloodstream (MTP means microsomal triglyceride transfer

*ATP-CL*

Malonyl-CoA *ACC FAS*

NADPH NADP

NADP NADPH

Palmitate

Stearate

Oleate

Diacylglycerol

TAG *DGAT1 DGAT2*

TAG

*MTP*

VLDL

VLDL

*RE*

Lysophosphatidic acid

Glycerol-3P *GPAT*

*SCD-1*

*ELOVL6*

Acetyl-CoA

Fig. 1. Scheme of de novo lipogenesis from glucose. Once inside the hepatocyte, glucose is metabolized on one hand through glycolysis to pyruvate (GK means

Pyruvate *L-PK*

Oxaloacetate

Malate Oxaloacetate

*MDH*

Malate

*MDH*

*EM*

protein). Original artwork.

NADP

*Hepatocyte*

*Blood*

NADPH
