Enzyme reactions and fatty acids

The liver is the main organ deputed to the synthesis of fatty acids (lipogenesis); it has the “vocation” of initiating the cascade of enzymatic reactions provided for lipogenesis. Without fats, no cell can live, and for this reason, the liver is an indispensable organ.

Lipogenesis involves three consecutive stages (see figure):

• the ex-novo synthesis of palmitic acid, a saturated fatty acid (16 carbon atoms);
• the two-unit elongation reaction of the palmitic acid structure, transformed into stearic acid (18 carbon atoms). Palmitic acid and stearic acid are the two main saturated fatty acids in our cells, and the cell membrane of the hepatocyte (as shown in the table in the article www.lipinutragen.it/en/liver-and-its-cells-hepatocytes/) also has an amount of up to 40-45% of its total components;
• the subsequent transformation, which is very important and necessary precisely for hepatic metabolism, of stearic acid into oleic acid (monounsaturated fatty acid with 18 carbon atoms) by insertion of a double bond (in technical terms, enzymatic desaturase; see figure shown as delta-9 desaturase or SCD-1).

It is highlighted that saturated fats, although necessary for the formation of cells and the cell membrane, must necessarily be transformed into monounsaturated fats to allow the two components (saturated and monounsaturated) to mix and ensure adequate flow and permeability properties, which are necessary for vital functions.

Hepatic metabolism and membrane composition

In hepatic metabolism, transformation takes on particular significance, as seen in the figure taken from a major review in 2009 [1]. In fact, the ability to “desaturate” has an impact on adaptation and metabolic flexibility of the liver cell.

If the hepatocyte contains sufficient proportions of monounsaturates, the cell membrane remains functional for metabolism, allows adaptation to all demands, and if the fat load increases, lipid accumulation evolves into a condition of steatosis, but without destructive effects.

In the case of impediment of saturated fat transformation, on the other hand, there is an increase in the saturated component over the monounsaturated component, with structural change of the hepatocyte and consequent cellular damage, corresponding to a condition of steatohepatitis. In this condition, there will also be an imbalance in favor of inflammatory-type signaling, which increases the destructive rather than regenerative potential of this very important cell.

Lipidomic analysis and liver status interpretation

To know how the liver is functioning, whether it is in metabolic homeostasis or whether it has developed metabolic or inflammatory issues, health experts have at their disposal an analytical tool that accurately reports the composition of the hepatocyte: lipidomic analysis of the mature red blood cell (performed in our Lipidomics Laboratory with exclusive robotic equipment, according to ISO 17025 accredited method).

The molecular information present in the outcome of membrane lipidomic analysis is the complementary aspect to biochemical-clinical (for GOT-GPT-ALT transaminase values, C-reactive protein, etc.) and diagnostic (such as ultrasonography) examinations to assist therapeutic and/or nutritional strategies.

Only by supporting the balance of the lipid pool can the regenerative potential of the hepatocyte be fully expressed, sustaining metabolic demands at all ages and occasions (as described in the article www.lipinutragen.it/en/liver-and-its-cells-hepatocytes/).

Essential bibliography:

[1] Alkhouri,N.; Dixon, L.J.; Feldstein, A.E. Lipotoxicity in Nonalcoholic Fatty Liver Disease: Not All Lipids Are Created Equal Expert Rev Gastroenterol Hepatol. 2009, 3, 445–451
[2] Ferreri, C.; Chatgilialoglu, C. Membrane Lipidomics for Personalised Health, page 39, Wiley, 2015

Read more in LipiMagazine:

• NON-ALCOHOLIC HEPATIC STEATOSIS: www.lipinutragen.it/en/liver-organ-not-to-be-overloaded/
• THE SCIENTIFIC VALIDITY OF MEMBRANE LIPIDOMICS: www.lipinutragen.it/en/lipidomic-membrane-analysis/

Article edited by the Lipinutragen Editorial Group in collaboration with Dr. Carla Ferreri, CNR Director in Bologna and Scientific Director of Lipinutragen

The information reported should in no way replace the direct relationship between health professional and patient.

Photo: 123RF Archivio Fotografico: 178359670 : ©mol4un

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Molecular balance to maintain good liver function

The liver is made up of cells, the hepatocytes, which are 80 percent of its total mass. These cells are veritable factories for the formation and transformation of molecules, whose mitochondria work by producing metabolites and energy, supplying, among other things, high amounts of albumin, coagulation factors and other proteins that are found in the circulation. Liver products also include bile salts, which come from cholesterol metabolism.

A look at cell activity ^[1]

Another role played admirably by hepatocytes is detoxification, which is the transformation through a veritable enzymatic arsenal (collectively called P450 enzymes) of toxic molecules that arrive from throughout the body through the venous (portal vein) bloodstream. This valuable work allows toxic products to be converted into products that can no longer do harm and can be eliminated from the body through excretion pathways.  This transformation also takes place to eliminate drugs.

In this continuous “metabolic” work, the liver may become fatigued, but it is important to note that this tissue has higher regenerative capacity than other tissues, i.e., it is able to fully regenerate cell mass and function after being affected by different types of problems. It can be said that under normal conditions and without alteration of the natural balance, the liver has a “slow” turnover, between cells that have reached the end of their life and cells that divide to generate new cells (only 1-2% of all cells divide). The time can be estimated in months with an average life span of 180 days.

If it is subjected to a series of events of an infectious, traumatic, or even metabolic or vascular nature, the liver can accelerate the formation of new cells; for example, interestingly, after resection of part of this organ, it is able to rebuild its initial mass. This expresses the enormous potential for liver regeneration, which does not have to be altered and can respond naturally by repairing damage.

Liver fatigue and impact on metabolism

The liver, in its fundamental role as a “molecule factory,” can also go into fatigue with issues that impact overall metabolism. In this case, the most predominant origin of liver problems lies in dysregulation of fat metabolism.

When it comes to lipids, it is clear that further investigation with cell membrane lipidomic analysis can allow us to pinpoint exactly where the balance of hepatic functioning is broken, giving substantial help in framing the liver condition and also suggesting rebalancing strategies.

Recall that membrane lipidomic analysis is performed on the mature red blood cell (average life span 120 days), a cell representative of tissues throughout the body, but in particular a faithful mirror of the composition of the hepatocyte, to which it is virtually equal as a distribution of saturated, monounsaturated and polyunsaturated fats (tab from [2] work in bibliography).

Liver cell growth and replication underlie the resolution of most liver damage; it is important to understand how to succeed in maintaining the regenerative potential of this organ over time by supporting the formation of a balanced lipid pool, a prerequisite for the formation of fully functioning cell membranes.

Bibliography:

[1] Stanger, B. Z. Annu. Rev. Physiol. 2015, 77:179–200
[2] Ferreri, C.; Chatgilialoglu, C. Membrane Lipidomics for Personalised Health, page 39, Wiley, 2015

Article edited by the Lipinutragen Editorial Group in collaboration with Dr. Carla Ferreri, CNR Director in Bologna and Scientific Director of Lipinutragen

The information reported should in no way replace the direct relationship between health professional and patient.

Photo: 123RF Archivio Fotografico: 197311168 : ©zodyak53

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NON-ALCOHOLIC HEPATIC STEATOSIS

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide (about 25% of the general population), and among patients, a not insignificant percentage (3-5%) develops non-negligible steatohepatitis. alcoholic (NASH), characterized by damage to hepatocytes, inflammation and fibrosis, which increase the risk of developing cirrhosis and hepatocellular carcinoma.
At the base of the pathogenesis of NAFLD there is an accumulation of fats, in particular of triglycerides (TG) in the liver. It is therefore not surprising that most people with NAFLD have conditions such as visceral obesity (fat accumulation within the waist), hypertension, hyperlipidemia, and diabetes.
However, the mechanisms by which a minority of patients develop a more severe phenotype than others are still not fully understood. In a recent review carried out by the University of Perugia and the Polytechnic of Ancona, together with the Scientific Division of Lipinutragen, it is clear that, in addition to the accumulation of TG, the main cause of the progression of the steatotic form in steatohepatitis was determined in the LIPOTOXICITY, or in the accumulation of specific classes of lipids (free fatty acids, ceramides, cholesterol, bile acids) which act as harmful agents [1]. These species, defined as “lipotoxic”, influence cell behavior through multiple mechanisms that induce the activation of cell death and oxidative stress receptors.

ROLE OF FREE FATTY ACIDS (FFA) IN LIPOTOXICITY

The most studied mechanisms underlying the progression from NAFLD to NASH are those that lead to the release and transformation of lipid species defined as “neutral” (i.e. TG) into Free Fatty Acid (FFA).
In particular, it appears that more than the quantity of FFA that accumulate in the liver, it is their quality that influences the lipotoxic events.
Among these, saturated fatty acids (SFA), such as palmitic acid and stearic acid, have shown greater toxicity than monounsaturated fatty acids (MUFA), such as oleic acid, which instead show a protective role for the cell [2]. Along with MUFAs, polyunsaturated fatty acids (PUFAs) of the omega-3 series also have a proven protective activity for the liver. As evidenced by recent clinical studies [3-5], omega-3 PUFAs, in addition to reducing TG levels in plasma and liver, reduce transaminase (ALT) values ​​and in general lead to an improvement in ultrasound parameters in liver in both adult and pediatric NASH patients.
Conversely, an accumulation of PUFA of the omega-6 series, and in particular of arachidonic acid (AA), favors the formation of inflammatory molecules, charging the process of lipotoxicity.

EVIDENCE OBTAINED WITH THE LIPIDOMIC ANALYSIS OF MATURE ERYTHROCYTES

The growing understanding of these lipid anomalies through lipidomic technologies, such as membrane lipidomic analysis of mature red blood cells (GRM), enrich the understanding of the phenomenon by directly evaluating the presence of lipotoxicity as a key pathogen at the cellular level.
An important point in favor of the use of erythrocytes, as a reporter for liver disease, is the similarity of their composition in terms of membrane fatty acids with that of hepatocytes:

• SFA: 43% in the GRM versus 42% in the liver
• MUFA: 23.0% in the GRM versus 23.8% in the liver
• Omega-6 PUFA: 27.6 in the GRM versus 27.4% in the liver
• Omega-3 PUFA: 5.7% in the GRM versus 4.6% in the liver [6].

The average life span of cells, 120 days for erythrocytes and 180 days for hepatocytes, is also a clear indication of similar metabolism among the fatty acids that make up the phospholipids of their membranes.

SCIENTIFIC EVIDENCE AND ROLE OF NUTRITION

Recent studies report the possibility of treating NAFLD and NASH subjects by exploiting the benefits of a dietary supplement, in particular with vitamin E and PUFA of the omega-3 series [7-9]. Vitamin E, in fact, represents the most important molecule “for blocking” the oxidative cascade caused by free radicals. In fact, it is now recommended in clinical guidelines of the EU, US and Asia as a therapy for NASH in non-diabetic patients [8-9]. While, as regards the omega-3 PUFAs, DHA represents a promising molecule to prevent the progression of the disease to NASH [7] thanks to its anti-inflammatory activity also acting at the level of the membranes, improving their plasticity and fluidity.
From these premises, clinical studies have been carried out that have also explored the potential of multivitamin formulations containing DHA, as the main component, in the therapy of pediatric NASH. The results show a marked improvement in the metabolic, ultrasound and histological parameters of the liver. The results of this and other studies confirm the importance of PUFA as biomarkers for a non-invasive diagnosis of NASH, describing for the first time its importance for verifying the effectiveness of what we can define as a “DHA therapy”. In light of the above, it would be even more important to customize the lipid therapy and also to follow it as efficacy, both clinical and molecular, over time by performing the membrane lipidomic analysis of the GRM. The knowledge is there, the diagnostic tool too, so it is only time to adapt the protocols, taking into account that the analysis is now performed by the Lipidomics Lipinutragen Laboratory with an ISO 17025 accredited method, therefore with the appropriate specifications for the certainty of the data obtained.

Bibliography:

• G. Svegliati-Baroni, I. Pierantonelli, P. Torquato, R. Marinelli, C. Ferreri,
C. Chryssostomos, D. Bartolini., F. Galli. Lipidomic biomarkers and mechanism of lipotoxicity in non-alcoholic fatty liver disease, Free Radical Biology and Medicine 144 (2019) 293–299.
• Y. Akazawa, S. Cazanave, J.L. Mott, N. Elmi, S.F. Bronk, S. Kohno, M.R. Charlton, G.J. Gores.
Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J. Hepatol., 52 (4) (2010), pp. 586-593.
• C. Della Corte, G. Carpino, R. De Vito, C. De Stefanis, A. Alisi, S. Cianfarani, D. Overi, A. Mosca, L. Stronati, S. Cucchiara, M. Raponi, E. Gaudio, C.D. Byrne, V. Nobili. Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency: results from a single centre trial. PLoS One, 11 (12) (2016), Article e0168216.
• E. Zohrer, A. Alisi, J. Jahnel, A. Mosca, C. Della Corte, A. Crudele, G. Fauler, V. Nobili.
Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial. Appl. Physiol. Nutr. Metabol., 42 (9) (2017), pp. 948-954.
• P. Torquato, D. Giusepponi, A. Alisi, R. Galarini, D. Bartolini, M. Piroddi, L. Goracci, A. Di Veroli, G. Cruciani, A. Crudele, V. Nobili, F. Galli. Nutritional and lipidomics biomarkers of docosahexaenoic acid-based multivitamin therapy in pediatric NASH. Sci. Rep., 9 (1) (2019), p. 2045.
• L. Lauritzen, H.S. Hansen, M.H. Jorgensen, K.F. Michaelsen. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog. Lipid Res., 40 (1–2) (2001), pp. 1-94
• V. Nobili, A. Alisi, G. Musso, E. Scorletti, P.C. Calder, C.D. Byrne. Omega-3 fatty acids: mechanisms of benefit and therapeutic effects in pediatric and adult NAFLD. Crit. Rev. Clin. Lab. Sci., 53 (2) (2016), pp. 106-120.
• F. Galli, A. Azzi, M. Birringer, J.M. Cook-Mills, M. Eggersdorfer, J. Frank, G. Cruciani, S. Lorkowski, N.K. Ozer. Vitamin E: emerging aspects and new directions.
• V.W. Wong, S. Chitturi, G.L. Wong, J. Yu, H.L. Chan, G.C. Farrell. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol. Hepatol., 1 (1) (2016), pp. 56-67.

Article by the Editorial team of Lipinutragen

The information given must in no way replace the direct relationship between health professional and patient.

Photo: 123RF Archivio Fotografico: 112228944 ©lightfieldstudios / 123rf.com | 106657631  ©ismagilov / 123rf.com

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