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How dangerous is fat in the liver?

How dangerous is fat in the liver?

What is the fat in the liver?

The liver is the main organ for body detoxification, it holds the main role in metabolic homeostasis and is an important factor in the synthesis, metabolism, storage, and redistribution of carbohydrates, proteins, and lipids.

The processed foods around us in abundance, toxins and environmental stress, the rapid increase in obesity around the world, are related to the increase in the prevalence of non-alcoholic fatty liver disease (NAFLD), also known as fatty infiltration, making it the most common liver disease in Western societies.

To understand the pathogenesis of NAFLD, we need to look at the basic physiological mechanisms of liver metabolism of lipids and glucose.

Fat infiltration (NAFLD) is characterized by fat accumulation within the hepatocytes and can develop into non-alcoholic steatohepatitis (NASH). Lipids that accumulate in the liver are derived from fatty acids circulating in the blood and which have the property of inducing peripheral lipolysis dysfunction because they exhibit insulin resistance.

Fatty acids are shifted into the hepatocyte mainly by membrane-bound transport proteins. De novo lipogenesis also contributes further to hepatic steatosis. This hepatocellular accumulation of lipotoxic intermediates causes hepatic resistance to insulin.

The accumulation of hepatocellular lipids predisposes to:
1. overproduction of active oxygen species (ROS)
2. stress in the endoplasmic gland
3. lipotoxicity

Scientist Yosinori Osummi was awarded the Nobel Prize in Medicine in 2016 because he discovered the normal process of "autophagy", that is, the mechanisms that alter and recycle cellular components that are no longer necessary or not working properly. It took 30 years of research and publications to understand this particular mechanism whose mutations in its genes can cause various diseases and conditions.

One of these is the pathogenesis of non-alcoholic steatohepatitis. Individual stages in lipid hepatic metabolism are orchestrated by a subtle interaction of hormones, nuclear receptors, intracellular signaling pathways, and transcription factors. The signaling of insulin plays an important role in regulating the metabolism of free fatty acids, highlighting the close relationship between lipids and glucose metabolism. Insulin affects de novo lipogenesis at multiple levels. Insulin, along with other mediators, suppresses "autophagy" within hepatocytes, inducing lipogenesis and suppressing lipid degradation in satiety.

The metabolism of lipids begins with the intestinal absorption of dietary fats. In order to cross the intestinal lumen into the plasma, the lipids are emulsified and hydrolyzed into the lumen. A healthy liver is vital for the intestinal absorption of lipids through the bile acids synthesized in the hepatocytes and secreted into the gallbladder to emulsify the lipid droplets their amphiphilic properties make them accessible to hydrolysis by lipase.

Hydrolyzed lipids are then absorbed by the enterocytes, where the lipids are reconstituted and packaged into lipoprotein particles (i.e., generalized chylomicrons). Generated chylomicrons are secreted into the lymphatic system, where they override the liver and enter the circulation within 2 hours of taking food. Free fatty acids derived from lipolysis in adipose tissue are actively taken from various insulin-free fatty acid transporters and nuclear receptor signaling. Under physiological conditions, most of the fatty acids are oxidized endo-mitochondria and provide ATP and acetyl-CoA for the citric acid cycle. Triglycerides derived from de novo lipogenesis are either stored in lipid droplets or packaged in VLDL and enter the blood.

Acetyl-CoA for de novo lipogenesis is provided by the pyruvate dehydrogenase complex, which catalyzes the oxidation of the pyruvate, the final glycolysis product. Under normal conditions, β-oxidation of short, medium, and long-chain fatty acids are degraded in mitochondria. Malonyl-CoA, an intermediate of lipogenesis, inhibits the carnitine palmitoyltransferase-CPT1 and thus the oxidation of fatty acids in the mitochondria. With the abundance of fatty acids and insulin resistance, long-chain and long-chain fatty acids (VLCFA) are oxidized in hyperoxides and the endoplasmic reticulum.

This leads to an abundance of metabolites that induce the formation of ROS and contribute to lipotoxicity. Increased peripheral lipolysis, upregulation of fatty acid transporters, increased de novo lipogenesis, and a switch from mitochondrial β-oxidation to hyperoxides and β-oxidation are favored by fatty acid toxicity and release of ROS. This leads to induction of hepatocyte apoptosis, invasion, and activation of inflammatory cells, as well as fibrogenesis.

In summary, liver fatty acids are either derived from:
1. endogenous lipogenesis,
2. or released from "autophagy"
3. or derived from the free fatty acids of the plasma reservoir, via active uptake into the hepatocytes

Depending on the metabolic status, the fatty acids are then either processed and stored or rapidly metabolized. Indeed, beta-oxidation is the main source of energy during the fasting state. After intestinal absorption, glucose reaches the hepatocytes through the portal vein.

There is a close relationship between lipid metabolism and glucose which is indicated by the fact that nuclear receptors are also important mediators of insulin signaling and given de novo lipogenesis occurring under anabolic status. The existence of such a ligand is further supported by the fact that insulin stimulates the expression of fatty acids through the kinase 3 phosphoinositide pathway. As their fatty acids and metabolites are the main cause of lipotoxicity and favor the formation of ROS, they are stored for future use as triglycerides. The triglycerides are then either stored in lipid droplets within the hepatocytes or processed for VLDL.

In the postprandial state, blood glucose is taken up by hepatocytes via the type 2 glucose transporter (GLUT2). In contrast to GLUT4, expressed by muscles and adipose tissue, the expression and activity of GLUT2 is independent of insulin signaling. In pancreatic islet cells, GLUT2 is also referred to as the "glucose sensor".

In fasting, the liver supplies the body with energy through the glycogen breakdown process or after prolonged fasting through gluconeogenesis. Hepatic gluconeogenesis occurs during prolonged fasting and starts intramitochondrial by the induction of pyruvate carboxylase to an abundance of acetyl CoA. Interestingly, due to CPT-1 palmitoyltransferase hepatic carnitine inhibition, the oxidation of fatty acids in mitochondria greatly suppresses hepatic gluconeogenesis. The procedures again demonstrate the close interdependence between gluconeogenesis and hepatic lipid metabolism.

Fatty liver is the most widespread condition of the liver in western societies.

It is presented with a wide range ranging from simple steatosis or non-alcoholic fatty liver (NAFL) to fully developed steatohepatitis with or without fibrosis (scarring). This may develop into fibrosis with an increased risk for developing liver disease or hepatocellular carcinoma (HCC).

Hepatic steatosis is defined as the intrinsic accumulation of triglycerides.

Additionally, abundant fatty acids are the cause of lipotoxicity, by inducing the release of ROS, which causes inflammation, apoptosis, which can potentially develop into fibrogenesisObesity increases TNFα production in adipocytes, facilitating adipocyte insulin resistance and increasing lipolysis rate. Thus, the release of free fatty acids increases in obese individuals and accounts for most of the fat lipid in the fatty liver. Fatty acids induce TNFα production, and hepatic expression of the TNF receptor correlates with the gravity of the disease in the fatty liver.

Activation of the TNF receptor increases gene expression, which induces hepatic lipogenesis and lipid accumulation. Since TNFα-mediated effects are antagonized by adiponectin, adiponectin receptors are actually downstream in pathologies. Activation of TNFα is further paralleled with the expression of receptor death, which facilitates the activation of the cataract of exogenous apoptosis.

Apoptosis is indeed the dominant form of hepatocellular damage. As previously mentioned, the accumulation of fatty acids also leads to stress induction in the endoplasmic reticulum and ROS formation, also promoting hepatic damage. Hepatic lipids and glucose metabolism are closely linked to inflammatory, proliferative, and apoptotic signaling within the liver.

In the liver, catabolic and anabolic pathways can hardly be separated. They share intermediate metabolites and receptor signaling and keep pace with the pathogenesis of the most common liver problems. Improved understanding of these key mechanisms is therefore imperative for the increasing prevalence of obesity and metabolic syndrome.

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