Direct Versus Indirect Effect of Amino Acids on Hepatokines

Liver hormones are key metabolic regulators and increased in metabolic diseases, including fatty liver disease. The underlying mechanisms driving the elevated levels are currently unknown and presents a major challenge in understanding the interplay between liver hormones and fatty liver disease. The project aims to investigate what stimulates the liver to secrete its hormones and why the secretion is increased in patients with fatty liver disease. The investigator (Associate Prof. Nicolai J Wewer Albrechtsen) will investigate the direct and indirect effects of an amino acid amino infusion on the secretion of hepatokines in individuals with and without metabolic dysfunction-associated steatotic liver disease (MASLD).

The liver secretes signaling molecules, (termed hepatokines) to the blood circulation which are powerful metabolic regulators and biomarkers of liver disease. Some of the more studied hepatokines include follistatin, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) and they have been sown to improve glucose tolerance, reduce liver fat content and regulate appetite.

In dysregulated metabolic conditions, including obesity, MASLD and type 2 diabetes, the circulating levels of hepatokines are increased. It could be speculated that the body increases hepatokine levels as a feedback mechanism to combat dysregulated metabolism. However, the underlying mechanisms driving the elevated levels in metabolic disease are currently unknown. The secretion of follistatin, FGF21 and GDF15 from the liver has been suggested to be stimulated by glucagon and amino acids. In dysregulated metabolic diseases, circulating levels of glucagon and amino acids are often increased and are highly dependent on hepatic steatosis. Increased levels of hepatokines observed in dysregulated metabolic individuals could therefore be attributed to an increase in circulating glucagon, amino acids, or a combination of both.

The study aims to explore the direct and indirect effect of amino acids on the regulation of hepatokines in individuals with and without MASLD. The study evaluates the acute effect of an amino acid infusion with and without a concomitant infusion of the somatostatin analogue octreotide to eliminate endogenous production of glucagon, thus isolating the direct effect of amino acids. ,

The investigators hypothesizes that an amino acid infusion will increase the secretion of hepatokines independent of glucagon.

Eligibility Criteria:
Group 1: (Lean controls)

Inclusion Criteria:

* Male or female between 25-65 years of age at time of screening
* Body mass index of 18.6-25 kg/m2

Exclusion Criteria:

* Contraindications for MRI-scan
* Severe liver disease (estimated by FIB4 score \> 3.25)
* Type 2 diabetes according to ADA criteria
* Significant history of alcoholism or drug/chemical abuse as per investigators judgement
* Amino acid related diseases
* Kidney disease
* Cardiac problems
* Cancer within the past 1 year
* Anemia
* Pregnancy or breast feeding
* Smoking
* Any medicine, acute illness (within the last two weeks) or other circumstances that in the opinion of the investigator might endanger the participants' safety or compliance with the protocol

Group 2 (individuals with hepatic steatosis):

Inclusion Criteria:

* Male or female between 25-65 years of age at time of screening
* Body mass index of 25-40 kg/m2
* Hepatic non-alcoholic steatosis verified by liver biopsy, fibroscan or ultrasound

Exclusion Criteria:

* Contraindications for MRI-scan
* Severe liver disease (estimated by FIB4 score \> 3.25)
* Type 2 diabetes according to ADA criteria
* Significant history of alcoholism or drug/chemical abuse as per investigators judgement
* Amino acid related diseases
* Kidney disease
* Cardiac problems
* Cancer within the past 1 year
* Anemia
* Pregnancy or breast feeding
* Smoking
* Any medicine, acute illness (within the last two weeks) or other circumstances that in the opinion of the investigator might endanger the participants' safety or compliance with the protocol