Table 2.

Potential novel therapeutic targets for intervention.

Pathologic Process	Potential Therapeutic Targets	Mechanism of Action
Steatosis Decrease in fatty acid oxidation	CYP2E1 and PPAR-α	Ethanol upregulates CYP2E1 production resulting in hepatic oxidative stress, which in turn prevents up-regulation of PPAR-α, a nuclear hormone receptor, that regulates transcription of many genes involved in free fatty acid transport and oxidation.
Steatosis Increase in fatty acid uptake	SREBP-1c	Acetaldehyde upregulates SREBP-1c, a master transcription factor that upregulates the expression of genes encoding lipogenic enzymes, resulting in increased fatty acid synthesis.
	CB1, CB2	Endocannabimoids are also responsible for up-regulating SREBP-1c leading to increased fatty acid synthesis, but also mediate alcoholic liver injury through signaling through either of two cannabinoid receptors, CB1 and CB2. Signaling through CB1 worsens alcoholic liver injury while signaling through the CB2 confers a protective role in the development of steatosis.
	SIRT1	SIRT1, a NAD(+)-dependent class III protein deacetylase, also inhibits SREBP-1c activation decreasing fatty acid synthesis. SIRT1 agonists could be potentially be used to curtail the effects of ethanol on steatosis.
	Adiponectin, AMPK	AMPK, a serine-threonine kinase, inactivates the rate-limiting enzyme ACC in fatty acid synthesis. Inactivation of ACC leads to a reduction in the levels of malonyl Co-A, a precursor in fatty acid synthesis and an inhibitor of the rate-limiting enzyme CPT1, in fatty acid oxidation, resulting in less fatty acid synthesis and increased oxidation. While ethanol inhibits this pathway, adiponectin can confer protection by modulating this pathway.
Steatosis Autophagy	mTOR	Chronic alcohol consumption inhibits autophagy, leading to fat accumulation and. Inhibition of the mTOR signaling pathway inhibits progression to steatosis.
Steatohepatitis Bacterial translocation and the inflammatory cascade	LPS, TLR	Ethanol increases gut permeability resulting in translocation of bacterial products, such as LPS, into portal circulation, resulting in activation of Kupffer cells through TLR4 leading to production and release of pro-inflammatory cytokines. TLR antagonists have been proposed as potential therapeutic agents.
	IL-6, IL-10, STAT3	Kupffer cells secrete anti-inflammatory cytokines, IL-6 and IL-10, which bind STAT3 to curb inflammation and slow progression of liver injury.
Steatohepatitis Neutrophillic infiltration	IL-1, osteopontin, CXCL4, CXCL5, CXCL6	IL-1, osteopontin, CXCL4, CXCL5, and CXCL6 are chemokines that attract and activate macrophages.
Fibrosis Promotion of fibrosis	ERK1, ERK2, phosphinositide 3 kinase-Akt and JNK	ROS production stimulates collagen production though stimulation of pro-fibrogenic signaling pathways in HSCs including ERK1, ERK2, phosphinositide 3 kinase-Akt and JNK.
Fibrosis Inhibition of collagen degradation	metalloproteinases	ROS produced with heavy alcohol consumotion propagate collagen accumulation by preventing collagen degradation, through direct inhibition of metalloproteinases which degrade collagen.
Apoptosis and massive cell death	Caspase	Caspase inhibitors are known to inhibit apoptosis.
Innate immune response Neutrophil recruitment	IL-17, IL-8, CXCL1, ostepontin	IL-17 induces neutrophil recruitment by stimulating HSCs to secrete IL-8 and CXCL1. The modification of these chemokines may mediate neutrophil infiltration and attenuate alcoholic hepatitis. Osteopontin, an extracellular matrix protein, also contributes to neutrophillic recruitment, and is markedly upregulated in alcoholic hepatitis, and is an attractive target in considering new therapeutic agents.
Adaptive immune response T cells	Circulating T cells	Patients with alcoholic hepatitis have been found to have circulating T cells with antibodies to free-radical adducts
Intestinal dysbiosis	LCFA	Genomic and metabolomic analyses of intestinal bacteria revealed low levels of lactobacilli and reduced production of LCFA in those with alcoholic liver injury. Supplementation with LCFA restored eubiosis, intestinal barrier function, and reduced liver injury in mice.
Hepatic regeneration		The mechanism remains to be elucidated, but severe alcoholic hepatitis is marked by a failure of liver progenitor cells to progress past massive proliferation to maturation into mature hepatocytes. Agents to promote hepatic regeneration are being explored.

CYP2E1, cytochrome P450 2E1, PPAR-α: proliferator-activated receptor-α, SREBP-1c: sterol regulatory element-binding protein-1c, CB1: cannabinoid receptor 1, CB2: cannabinoid receptor 2, SIRT1: sirtuin 1, AMPK: AMP-activated protein kinase, mTOR: mammalian target of rapamycin, LPS: lipoplysaccharide, TLR: toll-like receptor, IL-6: interleukin-6, IL-10: interleukin-10, IL-1: interleukin-1, IL-17: interleukin-17, IL-8: interleukin-8, LCFA: long-chain fatty acids