Role of Elevated Intracellular S-Adenosylhomocysteine in the Pathogenesis of Alcohol-Related Liver Disease

Abstract

Background: The earliest manifestation of alcohol-related liver disease (ALD) is steatosis, characterized by the accumulation of lipid droplets (LDs) in hepatocytes. Findings from our laboratory have indicated that many pathological changes, including steatosis, correlate with the alcohol-induced hepatocellular increases in S-adenosylhomocysteine (SAH). Based on these considerations, we hypothesized that an experimental increase in intracellular SAH alone will result in similar steatotic changes to those seen after alcohol exposure. Methods: Freshly isolated rat hepatocytes grown on collagen-coated plates were exposed to serum-free medium containing 50 µmol/L oleic acid and varying concentrations of 3-deazaadenosine (DZA) to experimentally elevate intracellular SAH levels. Results: Overnight exposure to DZA treatment dose-dependently increased hepatocellular triglyceride accumulation, which was also evident by morphological visualization of larger-sized LDs. The rise in triglycerides and LDs accompanied increases in mRNA and protein levels of several LD-associated proteins known to regulate LD number and size. Furthermore, DZA treatment caused a decline in the levels of lipases that prevent fat accumulation as well as increased the expression of factors involved in lipogenesis and fatty acid mobilization. Collectively, our results indicate that the elevation of intracellular SAH is sufficient to promote fat accumulation in hepatocytes, which is similar to that seen after alcohol exposure.

Prognostic Value of Serum Exosomal AHCY Expression in Hepatitis B-Induced Liver Cirrhosis

“…The earliest manifestation of alcohol-related liver disease is steatosis, which is characterized by the accumulation of lipid droplets in liver cells. Arumugam et al ( 25 ) demonstrated that many pathological changes, including steatosis, are associated with the alcohol-induced increase in SAH hepatocytes. A study that investigated the impaired Hcy metabolism in patients with alcohol-related liver disease from Taiwan ( 26 ) showed that impaired Hcy metabolism may disrupt antioxidant status.…”

Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis

“…Fully differentiated 3T3-L1 adipocytes grown on coverslips were treated with different concentrations of DZA for 48 h. The processing for immunofluorescent staining was done as detailed in our previous publication 15 . Briefly, coverslips were rinsed with PBS and fixed with 4% paraformaldehyde followed by background quenching with 50 mM NH 4 Cl in PBS.…”

“…Total RNA was isolated from control and DZA-treated 3T3-L1 adipocytes as detailed previously 15 using PureLink RNA Mini Kit according to the manufacturer’s instructions. The concentration of the RNA and 260/280 nm optical density (OD) ratio was determined spectrophotometrically (NanoDrop Technologies, Wilmington, DE).…”

“…Based on these findings, we hypothesized that increased intracellular SAH alone can cause pathological changes in the adipocyte, as seen with alcohol administration. To test this, we exposed cultured differentiated 3T3-L1 adipocytes to 3-deazaadenosine (DZA), which causes intracellular SAH accumulation by blocking the activity of S-adenosylhomocysteine hydrolase 15 . We then examined the mechanisms underlying the effect of increased intracellular SAH to adipocyte dysfunction and the potential role in the progression of alcohol-associated fatty liver disease.…”

Oxidative Stress—A Key Player in the Course of Alcohol-Related Liver Disease

“…Refs. [ 149 , 150 , 151 ] Arumugam et al revealed in their study that increased intracellular SAH is sufficient to promote fat accumulation in hepatocytes, which resembles that seen after alcohol exposure [ 152 ]. Moreover, PRMT1 serves the role of transcriptional coactivator, participating in splicing and upstream of signal transduction [ 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 ].…”