A Unifying Hypothesis Linking Hepatic Adaptations for Ethanol Metabolism to the Proinflammatory and Profibrotic Events of Alcoholic Liver Disease

Abstract

The pathogenesis of alcoholic liver disease (ALD) remains poorly understood but is likely a multihit pathophysiological process. Here, we propose a hypothesis of how early mitochondrial adaptations for alcohol metabolism lead to ALD pathogenesis. Acutely, ethanol (EtOH) feeding causes a near doubling of hepatic EtOH metabolism and oxygen consumption within 2 to 3 hours. This swift increase in alcohol metabolism (SIAM) is an adaptive response to hasten metabolic elimination of both EtOH and its more toxic metabolite, acetaldehyde (AcAld). In association with SIAM, EtOH causes widespread hepatic mitochondrial depolarization (mtDepo), which stimulates oxygen consumption. In parallel, voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane close. Together, VDAC closure and respiratory stimulation promote selective and more rapid oxidation of EtOH first to AcAld in the cytosol and then to nontoxic acetate in mitochondria, since membrane-permeant AcAld does not require VDAC to enter mitochondria. VDAC closure also inhibits mitochondrial fatty acid oxidation and ATP release, promoting steatosis and a decrease in cytosolic ATP. After acute EtOH, these changes revert as EtOH is eliminated with little hepatocellular cytolethality. mtDepo also stimulates mitochondrial autophagy (mitophagy). After chronic high EtOH exposure, the capacity to process depolarized mitochondria by mitophagy becomes compromised, leading to intra- and extracellular release of damaged mitochondria, mitophagosomes, and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules. mtDAMPs cause inflammasome activation and promote inflammatory and profibrogenic responses, causing hepatitis and fibrosis. We propose that persistence of mitochondrial responses to EtOH metabolism becomes a tipping point, which links initial adaptive EtOH metabolism to maladaptive changes initiating onset and progression of ALD.

Ginseng (Panax ginseng Meyer) Oligopeptides Protect Against Binge Drinking-Induced Liver Damage through Inhibiting Oxidative Stress and Inflammation in Rats

“…Most studies of acute alcoholic liver damage have been performed in rodent models, which often divided into three types: single binge, intermittent heavy drinking and chronic alcohol exposure followed by episodes of binge, but there is no generally accepted method to date [ 26 , 31 , 32 ]. It was found that ethanol was administered at doses of 6–7 g/kg in rodents that produced peak blood ethanol concentrations that are similar to those that might be present in humans during acute alcoholism, which took into account differences in alcohol metabolism between rodents and humans [ 26 , 33 , 34 ]. Various factors cause abnormal lipid accumulation in lipid droplets in the liver, known as hepatic steatosis, which is the first and most common hepatic change induced by alcohol consumption [ 26 , 35 , 36 ].…”

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease

“…The pathogenesis of ALD is multifaceted and includes both direct and indirect factors, such as hepatocyte toxicity derived from ethanol (EtOH) metabolism, oxidative stress, DNA damage, metabolic alterations, and inflammation. Central to these disease processes is mitochondrial dysfunction which has been shown to be critical during both the onset and progression of ALD (Zhong and Lemasters, ). Mitochondria are essential organelles for the preservation of cell homeostasis.…”

The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer

“…Nonetheless, in ALD, there is an increase in the metabolization of ethanol to acetaldehyde by the cytosolic enzyme ADH and then from acetaldehyde to acetate by the mitochondrial enzyme aldehyde dehydrogenase [11] . In the long run, this will generate mitochondrial dysfunction, which is considered a critical step for the onset and progression of ALD [12] . Dysfunctional mitochondrial can undergo a fragmentation pathway to further be cleared by autophagy or promote the apoptotic cascade in sever liver injury by a multi-step process called "mitochondrial dynamics" controlled by the activity of the mitochondria shaping proteins (MSP) [13] .…”