Alcohol-Induced Liver Damage
Because the liver is a central detoxification organ, it is especially susceptible to damage from alcohol. Most heavy drinkers exhibit fatty liver or "ethanol-induced hepatic steatosis" and 40 to 50 percent of these can develop severe, life-threatening disease. How alcohol contributes to fatty liver is unclear, but Dr. McNiven's research team has shown that it occurs, in part, to a significant defect in lipid droplet (LD) breakdown.
The focus of this research is to understand how alcohol:
- Alters LD composition and function
- Disrupts LD breakdown by impairing autophagy
- Alters the association of LD-bound proteins that can contribute to normal fat catabolism
These publications describe the Cytoskeletal Membrane Dynamics Lab's work in alcohol-induced liver damage.
Schulze RJ, Drižytė K, Casey CA, McNiven MA. Hepatic lipophagy: New insights into autophagic catabolism of lipid droplets in the liver. Hepatology Communications. 2017;1:359.
The liver is a central fat-storage organ, making it especially susceptible to steatosis as well as subsequent inflammation and cirrhosis. The mechanisms by which the liver mobilizes stored lipid for energy production, however, remain incompletely defined. The catabolic process of autophagy, a well-known process of bulk cytoplasmic recycling and cellular self-regeneration, is a central regulator of lipid metabolism in the liver.
In the past decade, numerous studies have examined a selective form of autophagy that specifically targets a unique neutral lipid storage organelle, the lipid droplet, to better understand the function for this process in hepatocellular fatty acid metabolism. In the liver (and other oxidative tissues), this specialized pathway, lipophagy, likely plays a role in lipid turnover that is as important as conventional lipase-driven lipolysis. In this review, we highlight several recent studies that have contributed to our understanding about the regulation and effects of hepatic lipophagy.
Schulze RJ, Rasineni K, Weller SG, Schott MB, Schroeder B, Casey CA, McNiven MA. Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. Hepatology Communications. 2017;1:140.
Alcohol consumption is a well-established risk factor for the onset and progression of fatty liver disease. An estimated 90 percent of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol-induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism.
We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery. A mechanism is supported whereby ethanol exposure inhibits Rab7 activity, resulting in the impaired transport, targeting and fusion of the autophagic machinery with LDs, leading to an accumulation of hepatocellular lipids and hepatic steatosis.
Schott MB, Rasineni K, Weller SG, Schulze RJ, Sletten AC, Casey CA, McNiven MA. β-Adrenergic induction of lipolysis in hepatocytes is inhibited by ethanol exposure. The Journal of Biological Chemistry. 2017;14;292:11815.
β-adrenergic receptors stimulate the breakdown of fat in adipose tissue, but little is known about this receptor pathway in the liver. This study shows that β-adrenergic receptors stimulate fat loss in hepatocytes by recruiting cytoplasmic lipases (ATGL, HSL) to the surface of lipid droplets, which store intracellular fat. Unlike adipocytes, hepatocytes are sensitive to alcohol consumption which severely p erturbs the β-adrenergic pathway and breakdown of lipid droplets. This study provides novel insights into the pathogenesis of fat-induced alcoholic liver damage.
Rasineni K, Donohue TM Jr, Thomes PG, Yang L, Tuma DJ, McNiven MA, Casey CA. Ethanol-induced steatosis involves impairment of lipophagy, associated with reduced Dynamin2 activity. Hepatology Communications. 2017;1:501.
Lipid droplets (LDs), the organelles central to alcoholic steatosis, are broken down by lipophagy, a specialized form of autophagy. Here, we hypothesize that ethanol administration retards lipophagy by down-regulating dynamin 2 (Dyn2), a protein that facilitates lysosome re-formation, contributing to hepatocellular steatosis. Chronic ethanol administration slowed the rate of hepatocyte lipophagy, owing in part to lower levels of phosphorylated Src kinase available to activate its substrate, Dyn2, thereby causing depletion of lysosomes for LD breakdown.
Review published research articles from the Cytoskeletal Membrane Dynamics Lab related to alcohol-induced liver damage on PubMed.