Question

Excessive alcohol consumption has been strongly linked with fatty liver disease
(steatosis) and individuals with defective very low density lipoprotein cholesterol
(VLDL-c) are at higher risk of developing the condition. Explain how excessive
alcohol intake can be a risk factor of steatosis and the increase risk in alcohol
consumers with defective VLDL-c.

b. Triglycerides (TG) mobilization from adipocytes is crucial for survival during
starvation. A patient was found losing weight and showed drastic reduction of
energy (ATP) within few days of fasting. Further laboratory investigations
revealed that the patient lacks the ability to store fats, marked by high rate of TG
mobilization. Give the possible reasons for the increased lipolysis and also
explain how albumin level can be used as an indicator of lipolysis.

Answer 1

Excessive alcohol consumption is a serious global healthcare problem. The liver sustains the greatest degree of injury of tissue by heavy drinking as it is the primary site of ethanol metabolism. Chronic and excessive consumption of alcohol can produce a wide spectrum of hepatic lesions. The most characteristic of that are steatosis, hepatitis, and fibrosis etc. Steatosis is the earliest response to heavy drinking. It is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis. It is a more severe, inflammatory kind of liver injury. This stage of liver disease can lead to the development of fibrosis. During this there is excessive deposition of extracellular matrix proteins. The fibrotic responses begin with active pericellular fibrosis. It may progress to cirrhosis which is characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35% people develop advanced liver disease as a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.

Hepatic Alcohol Metabolism

Beverage alcohol is chiefly metabolized in the main parenchymal cells of the liver that make up about 70% of the liver mass. These cells express the highest levels of the major ethanol-oxidizing enzymes, alcohol dehydrogenase, that is located in the cytosol, and cytochrome P450 2E1, which resides in the smooth endoplasmic reticulum. Hepatocytes also express very high levels of catalase, an enzyme that inhabits peroxisomes. Catalase normally carries out the detoxification of hydrogen peroxide to water and then oxygen. However, when ethanol is present, catalase has an accessory role in ethanol metabolism by using hydrogen peroxide to oxidize ethanol to acetaldehyde. Ethanol oxidation by catalase is a relatively minor pathway in the liver, but has a larger ethanol-oxidizing function in the brain.

Alcohol’s Effects on Other Liver Cell Types:
Though hepatocytes comprise most of the liver mass, nonparenchymal cells, including Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells, and liver-associated lymphocytes make up the remaining 15% to 30% of the liver mass. These nonparenchymal cells interact with hepatocytes and with each other via soluble mediators and by direct cell-to-cell contact. Each and every liver cell type plays a specific role not only in normal hepatic physiology but also in initiating and perpetuating liver injury.

Spectrum of ALD

Heavy ethanol consumptions produce a big spectrum of hepatic lesions, the most characteristic being fatty liver or steatosis, hepatitis, and fibrosis. Steatosis is the earliest, most common response that develops in more than 90 percent of problem drinkers who consume 4 to 5 standard drinks per day over decades. However, steatosis also develops after binge drinking, defined as the consumption of 4 to 5 drinks in 2 hours or less. Steatosis was formerly considered a benign consequence of alcohol abuse. It is characterized by the deposition of fat, seen microscopically as lipid droplets, initially in the hepatocytes that surround the liver’s central vein, then progressing to mid-lobular hepatocytes, and finally to the hepatocytes that surround the hepatic portal vein. If the affected individual ceases drinking, steatosis is a reversible condition with a good prognosis. However, patients with chronic steatosis are more susceptible to fibrotic liver disease, because the presence of fat likely represents a greater risk for lipid peroxidation and oxidative damage.

B. Possible reasons for the increased lipolysis:
In the body, stores of fat are referred to as adipose tissue. In all these areas, intracellular triglycerides are stored in cytoplasmic lipid droplets. While lipases are phosphorylated, they can access lipid droplets and through multiple steps of hydrolysis, breakdown triglycerides into fatty acids and glycerol. Each step of hydrolysis leads to the one fatty acid removal. The first step and the rate-limiting step of lipolysis is carried out by adipose triglyceride lipase. This enzyme catalyzes the hydrolysis of triacylglycerol to diacylglycerol. Subsequently, hormone-sensitive lipase catalyzes the hydrolysis of diacylglycerol to monoacylglycerol and monoacylglycerol lipase catalyzes the hydrolysis of monoacylglycerol to glycerol.
Perilipin 1A is a key protein regulator of lipolysis in adipose tissue. This lipid droplet-associated protein, when it will deactivated, will prevent the interaction of lipases with triglycerides in the lipid droplet and grasp the ATGL co-activator, comparative gene identification 58 (CGI-58). When perilipin 1A is phosphorylated by PKA, it releases CGI-58 and then expedites the docking of phosphorylated lipases to the lipid droplet. CGI-58 can be further phosphorylated by PKA to assist in its dispersal to the cytoplasm. In the cytoplasm, CGI-58 can co-activate ATGL. ATGL activity is also impacted by the negative regulator of lipolysis, G0/G1 switch gene 2 (G0S2). When expressed, G0S2 acts as a competitive inhibitor in the binding of CGI-58. Fat-specific protein 27 (FSP-27) is also a negative regulator of lipolysis. FSP-27 expression is negatively correlated with ATGL mRNA levels.

Albumin level can be used as an indicator of lipolysis:
Albumin is the most abundant plasma protein in mammals. It plays an important role as a carrier for a variety of molecules. It possesses a high binding affinity for certain divalent cations, bilirubin, free fatty acids and other molecules, including xenobiotics. Due to albumin's high abundance and low molecular weight in relation to other major plasma proteins, it is responsible for about 80 percent of the total plasma oncotic pressure. Therefore, albumin is a key regulator of fluid distribution between the plasma and interstitial compartments in physiological conditions; although the absence of plasma albumin can be well compensated by increased liver secretion of other proteins which help to maintain nearly normal plasma oncotic pressure. Other less understood functions may also be ascribed to albumin, since its plasma depletion and redox modification have been demonstrated in several pathological conditions.