Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis

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Abstract Despite poor clinical outcomes there has been very limited response to therapies targeting hepatic inflammatory response especially in patients with malnutrition. Sarcopenia or skeletal muscle loss is a major component of malnutrition in AH and adversely affects clinical outcomes in these patients. Potential mechanisms by which sarcopenia can aggravate AH include reduced skeletal muscle metabolism of ethanol and impaired ammonia disposal due to decreased hepatic ureagenesis promoting ammonia induced hepatotoxicity. Even though targeting sarcopenia is an innovative approach with a mechanistic rationale to improve outcomes in patients with AH, this is not part of the therapeutic strategy in the ongoing NIAAA funded AlcHep network. Our published and preliminary data show dysregulated skeletal muscle protein homeostasis or proteostasis in response to ethanol in myotubes, mouse models, and human patients with alcoholic liver disease including AH. We also observed that ethanol exposure increases the skeletal muscle sensitivity to lipopolysaccharide (LPS) that results in impaired protein synthesis and increased autophagy and consequent sarcopenia. Interestingly, expression of canonical LPS receptor, TLR4, is increased in myotubes and in muscles from mice exposed to ethanol and patients with alcoholic liver disease. Consistently, P65NFkB, a downstream target of TLR4, is activated with increased. Expression of myostatin, a TGFβ superfamily member, a known transcriptional target of P65NFkB and negative regulator of skeletal muscle protein synthesis is also increased with LPS and ethanol. Interestingly, low molecular weight hyaluronic acid, especially fragments 35Kd and lower (HA35) have been reported to inhibit or modulate TLR4 signaling via specific receptors in a context specific manner. We made a novel observation that HA35 reversed ethanol and LPS induced reduction in myotube diameter, impaired proteostasis and signaling perturbations in both myotubes and mice exposed to ethanol. We will use HA35 initially in myotubes exposed to ethanol and mice chronically fed ethanol with binge (Gao model) that has significant sarcopenia and liver injury similar to that in human AH. In these preclinical studies, we will determine the molecular mechanisms by which HA35 reverses sarcopenia in AH. We will study the tissue responses to HA35 in ethanol-fed mice including skeletal muscle protein synthesis and breakdown and signaling responses. We will translate our preliminary and preclinical data into clinical application by treating human subjects with HA35, a food supplement, following acute ethanol exposure. We will also test if HA35 is beneficial in patients with moderate AH, a group of patients for whom there are currently no therapies available despite significant muscle loss and there are no ongoing clinical trials in moderate AH in the Alchep network. A data coordinating center will assist with these human studies. These studies will permit rapid therapeutic translation of our studies using HA35 as a novel, mechanism-based therapy for sarcopenia in AH, currently a major unmet need in this patient population.