Gastroenterology

1. Tuesday, May 23rd, 2023
7:00 PM – 8:00 PM ET
A Metabolic Approach to NASH Management:
Adipose Tissue as a Metabolic Organ
Supported by an educational grant from Novo Nordisk.
Provided by PCME and Rockpointe, in collaboration with Clinical Care Options, LLC

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3. Program Chairs
Stephen A. Harrison, MD, FACP,
FAASLD, COL (ret.) USA, MC
Visiting Professor of Hepatology
Radcliffe Department of Medicine
University of Oxford
Oxford, United Kingdom
Brent Tetri, MD
Professor of Internal Medicine
Division of Gastroenterology and
Hepatology
Saint Louis University,
St Louis, Missouri

4. Disclosures
The faculty reported the following relevant financial relationships or relationships to products or
devices they have with ineligible companies related to the content of this educational activity:
Brent Tetri, MD: consultant/advisor: 89Bio, Akero, Arrowhead, Boehringer Ingelheim, Bristol Myers Squibb,
Durect, GlaxoSmithKline, Glympse, Hepeon, High Tide, HistoIndex, Labcorp, LG Chem, Madrigal, Merck, Sagimet,
Senseion, Target RWE; stock/stock options: HepGene, HeptaBio; researcher (paid to institution): Bristol Myers
Squibb, HighTide, Intercept, Inventiva, Madrigal.
Stephen A. Harrison, MD, FACP, FAASLD, COL (ret.) USA, MC: researcher: Akero, Axcella Health, Cirius, CiVi
Biopharma, Cymabay, Enyo Pharma SA, Galectin, Galmed Research & Development, Genfit Corp, Gilead Sciences,
Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis,
Novo Nordisk, Poxel, Sagimet Biosciences, Viking; consultant/advisor: 89Bio, AgomAB, Akero, Alentis Therapeutics
AG, Altimmune, Arrowhead, Axcella Health, Boston Pharmaceuticals, B Riley FBR, BVF Partners LP, Canfite,
Chronwell, CiVi, Corcept, Cymabay, Echosens North America, Enyo Pharma, Fibronostics, Foresite Labs, Fortress
Biotech, Galectin, Galmed Research, Genfit Corp, Gilead Sciences, GNS, Hepion, Hightide Therapeutics, HistoIndex
PTE LTD, Indalo, Inipharm, Intercept, Ionis, Kowa Research Institute, Madrigal, Medpace, Metacrine, Microba,
NGM Biopharmaceuticals, Northsea Therapeutics, Novo Nordisk, Nutrasource, PathAi, Perspectum Diagnostics,
Piper Sandler, Poxer, Prometic Pharma, Ridgeline, Sagimet, Sonic Incytes Medical Corp, Terns, Viking Therapeutics;
stock/stock options: Akero Therapeutics, Chronwell, Cirius Therapeutics, Galectin Therapeutics, Genfit Corp,
Hepion, HistoIndex, Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics B.V, Sonic Incytes Medical Corp.

5. Learning Objectives
 Describe the metabolic nature of NASH pathophysiology
 Explain the relationship between NASH, obesity, and diabetes
 Determine appropriate strategies for early intervention and treatment
in patients with NASH
 Evaluate emerging metabolic therapies for the management of patients
with NASH

6. Slide credit: clinicaleducationalliance.com
Kahn. JCI 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Adipose Tissue as a Metabolic Organ
Metabolic flux
Insulin action/resistance
Metabolites
FFAs, BCAA, others
Inflammation
Insulin resistance
Inflammatory
mediators
TNF, IL-6, MCP-1,
resistin, adipsin,
RBP4
Regulation of appetite
Energy expenditure
Metabolism
Peptides, hormones,
growth factors
Leptin, adiponectin,
BMPs, FGF21, GDFs,
Nrg4
Gene expression in liver,
macrophages, and other tissues
Circulating
exosomal miRNAs
miR-99b, miR-155, others
Insulin sensitivity
Insulin secretion
Thermogenesis
Novel signaling lipids
FAHFAs, di-HOMEs
Binding proteins and precursors
Angiotensinogen, PAI-1, FABP4,
apelin, asprosin
Vascular integrity
Blood flow and clotting

7. Slide credit: clinicaleducationalliance.com
Kahn. JCI 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Adipose Tissue as a Metabolic Organ
Metabolic flux
Insulin action/resistance
Metabolites
FFAs, BCAA, others
Inflammation
Insulin resistance
Inflammatory
mediators
TNF, IL-6, MCP-1,
resistin, adipsin,
RBP4
Regulation of appetite
Energy expenditure
Metabolism
Peptides, hormones,
growth factors
Leptin, adiponectin,
BMPs, FGF21, GDFs,
Nrg4
Gene expression in liver,
macrophages, and other tissues
Circulating
exosomal miRNAs
miR-99b, miR-155, others
Insulin sensitivity
Insulin secretion
Thermogenesis
Novel signaling lipids
FAHFAs, di-HOMEs
Binding proteins and precursors
Angiotensinogen, PAI-1, FABP4,
apelin, asprosin
Vascular integrity
Blood flow and clotting

8. Slide credit: clinicaleducationalliance.com
Kahn. JCI 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Adipose Tissue as a Metabolic Organ
Metabolic flux
Insulin action/resistance
Metabolites
FFAs, BCAA, others
Inflammation
Insulin resistance
Inflammatory
mediators
TNF, IL-6, MCP-1,
resistin, adipsin,
RBP4
Regulation of appetite
Energy expenditure
Metabolism
Peptides, hormones,
growth factors
Leptin, adiponectin,
BMPs, FGF21, GDFs,
Nrg4
Gene expression in liver,
macrophages, and other tissues
Circulating
exosomal miRNAs
miR-99b, miR-155, others
Insulin sensitivity
Insulin secretion
Thermogenesis
Novel signaling lipids
FAHFAs, di-HOMEs
Binding proteins and precursors
Angiotensinogen, PAI-1, FABP4,
apelin, asprosin
Vascular integrity
Blood flow and clotting

9. Slide credit: clinicaleducationalliance.com
Adipose Tissue as a Metabolic Organ: Adiponectin
1. Roy. Cell Biosci. 2021;11:77. 2. Reprinted from Formolo. Brain Plasticity. 2022;8:79 with permission from IOS Press.
https://content.iospress.com/articles/brain-plasticity/bpl220138.
Regulation of Neuronal Plasticity by Adiponectin Signaling2
Tissue-Specific Adiponectin Signaling1
Adiponectin
Endothelial cells
↑Differentiation
↑Migration
↑eNOS Activity
↓Oxidative stress
↓Adhesion molecules
↓Apoptosis
Cardiomyocyte
↓Hypertrophy
↓Inflammation
↓Apoptosis
Bone
↑Osteoblastogenesis
↓Osteoclastogenesis
VSMCs
↑Migration
↑Proliferation
↑Apoptosis
Pancreatic β-cells
↑Glucose-induced
insulin secretion
↑β-cell survival
↓Apoptosis
Liver
↓Gluconeogenesis
↓Lipogenesis
↓Triglycerides
↓Ceramides
Skeletal muscle
↑Fatty acid oxidation
↑Insulin-induced
glucose utilization
↓Triglycerides
Protein synthesis
(late LTP maintenance)
Cellular growth
(spinogenesis)
TSC1/2
PPARα
APPL1
PI3K
P
AMPK
P
Nucleus
Mitochondrion
Adiponectin
AdipoR1/2
Glutamate
NMDAr Insulin Receptor
Insulin
G
G
Ins
Ins
Ins
G
Akt
IRS
Energetic homeostasis
during synaptic activity
mTORC1
Akt
CREB
APPL1
P

10. Slide credit: clinicaleducationalliance.com
Adipose Tissue as a Metabolic Organ
 Plasma adiponectin levels with pioglitazone treatment in patients with
NASH (n = 47) vs controls (n = 20)
Gastaldelli. Aliment Pharmacol Ther. 2010;32:769.
Baseline Adiponectin Levels
*P <.001 vs NGT. †P <.01 vs IGT.
Plasma Adiponectin Concentration
vs Hepatic Insulin Sensitivity
5
4
3
2
1
0
4 8 12 16
Adiponectin (µg/mL)
All controls
Patients with NASH
Pioglitazone
Placebo
Hepatic
Insulin
(µmol/min
kg
mmol/L)
-1
Controls
NGT
Controls NASH NASH
T2DM
IGT
*†
*†
r = 0.52; P <.0001
16
14
12
10
8
6
4
2
0
Adiponectin
Concentration
(µg/mL)

11. Slide credit: clinicaleducationalliance.com
Stressed Adipose Tissue
Kahn. J Clin Invest. 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Preadipocyte
subtypes
Mature adipocyte
subtypes
Lipodystrophic
adipocytes
Resident
macrophages (M2)
Proinflammatory
macrophages (M1)
Distinct types of
macrophages
Stromovascular
cells
Insulin
receptors
Normal adipose development
Normal nutrition
Normal microbiome
Adipocyte growth factors
Normal adipose
development
Different adipocyte
populations and other
adipocyte precursors

12. Slide credit: clinicaleducationalliance.com
Stressed Adipose Tissue
Kahn. J Clin Invest. 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Preadipocyte
subtypes
Mature adipocyte
subtypes
Lipodystrophic
adipocytes
Resident
macrophages (M2)
Proinflammatory
macrophages (M1)
Distinct types of
macrophages
Stromovascular
cells
Insulin
receptors
Normal adipose development
Normal nutrition
Normal microbiome
Adipocyte growth factors
Healthy adipose expansion
Increased number of
small adipocytes
Low inflammation
Normal adipose
development
Different adipocyte
populations and other
adipocyte precursors
Adipose
expansion
Preadipocyte proliferation
Adipocyte hyperplasia

13. Slide credit: clinicaleducationalliance.com
Stressed Adipose Tissue
Kahn. J Clin Invest. 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Preadipocyte
subtypes
Mature adipocyte
subtypes
Lipodystrophic
adipocytes
Resident
macrophages (M2)
Proinflammatory
macrophages (M1)
Distinct types of
macrophages
Stromovascular
cells
Insulin
receptors
Normal adipose development
Normal nutrition
Normal microbiome
Adipocyte growth factors
Healthy adipose expansion
Increased number of
small adipocytes
Low inflammation
Metabolically unhealthy obesity
Insulin resistance
Ectopic fat deposits
Metabolic syndrome
Normal adipose
development
Adipose
expansion
Adipose
remodeling
More adipocyte hyperplasia
and hypertrophy
Changing adipose hormones
Inflammation
Preadipocyte proliferation
Adipocyte hyperplasia
↑MCP-1
FFA
↑di-HOMEs
↓FAHFAs
∆ Exosomal
miRNAs
↑Leptin
↓Adiponectin
∆ Other adipose
hormones
↑TNF-α,
IL-1β,
etc
Different adipocyte
populations and other
adipocyte precursors

14. Slide credit: clinicaleducationalliance.com
Stressed Adipose Tissue
Kahn. J Clin Invest. 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Preadipocyte
subtypes
Mature adipocyte
subtypes
Lipodystrophic
adipocytes
Resident
macrophages (M2)
Proinflammatory
macrophages (M1)
Distinct types of
macrophages
Stromovascular
cells
Insulin
receptors
Normal adipose development
Normal nutrition
Normal microbiome
Adipocyte growth factors
Healthy adipose expansion
Increased number of
small adipocytes
Low inflammation
Metabolically unhealthy obesity
Insulin resistance
Ectopic fat deposits
Metabolic syndrome
Normal adipose
development
Adipose
expansion
Adipose
remodeling
More adipocyte hyperplasia
and hypertrophy
Changing adipose hormones
Inflammation
Preadipocyte proliferation
Adipocyte hyperplasia
↑MCP-1
FFA
↑di-HOMEs
↓FAHFAs
∆ Exosomal
miRNAs
↑Leptin
↓Adiponectin
∆ Other adipose
hormones
↑TNF-α,
IL-1β,
etc
Different adipocyte
populations and other
adipocyte precursors

15. Slide credit: clinicaleducationalliance.com
Stressed Adipose Tissue
Kahn. J Clin Invest. 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Preadipocyte
subtypes
Mature adipocyte
subtypes
Lipodystrophic
adipocytes
Resident
macrophages (M2)
Proinflammatory
macrophages (M1)
Distinct types of
macrophages
Stromovascular
cells
Insulin
receptors
Normal adipose development
Normal nutrition
Normal microbiome
Adipocyte growth factors
Healthy adipose expansion
Increased number of
small adipocytes
Low inflammation
Metabolically unhealthy obesity
Insulin resistance
Ectopic fat deposits
Metabolic syndrome
Normal adipose
development
Adipose
expansion
Adipose
remodeling
More adipocyte hyperplasia
and hypertrophy
Changing adipose hormones
Inflammation
Preadipocyte proliferation
Adipocyte hyperplasia
↑MCP-1
FFA
↑di-HOMEs
↓FAHFAs
∆ Exosomal
miRNAs
↑Leptin
↓Adiponectin
∆ Other adipose
hormones
↑TNF-α,
IL-1β,
etc
Different adipocyte
populations and other
adipocyte precursors

16. Slide credit: clinicaleducationalliance.com
Stressed Adipose Tissue
Kahn. J Clin Invest. 2019;129:3990. Reproduced in accordance with https://creativecommons.org/licenses/by/4.0/.
Normal adipose development
Normal nutrition
Normal microbiome
Adipocyte growth factors
Healthy adipose expansion
Increased number of
small adipocytes
Low inflammation
Metabolically unhealthy obesity
Insulin resistance
Ectopic fat deposits
Metabolic syndrome
Normal adipose
development
Adipose
expansion
Adipose
remodeling
More adipocyte hyperplasia
and hypertrophy
Changing adipose hormones
Inflammation
Preadipocyte proliferation
Adipocyte hyperplasia
↑MCP-1
FFA
↑di-HOMEs
↓FAHFAs
∆ Exosomal
miRNAs
↑Leptin
↓Adiponectin
∆ Other adipose
hormones
↑TNF-α,
IL-1β,
etc
Lipodystrophy
Insulin resistance
Ectopic fat deposits
Metabolic syndrome
Genetic
Acquired/HIV
Genetic
Acquired/HIV
↑Leptin
↓Adiponectin
Different adipocyte
populations and other
adipocyte precursors

17. NASH Pathophysiology

18. Slide credit: clinicaleducationalliance.com
Genetic Factors in NAFLD/NASH
 Predisposing
‒ PNPLA3 I148M
‒ TM6SF2 E167K
‒ MBOAT7
‒ GCKR
 Protective
‒ HSD17B13
‒ MARC1
‒ CIDEB (loss of function mutations)
Pennisi. Hepatol Commun. 2022;6:1032.

19. Slide credit: clinicaleducationalliance.com
Genetics vs Role of Metabolic Comorbidities
 UK BioBank subjects (n = 266,687 with median f/u 9 yr)
 Risk of liver-related events based on polygenic risk score‒hepatic fat content (PRS-HFC*)
De Vincentis. Clin Gastroenterol Hepatol. 2022;20:658.
*Weighted scored based on PNPLA3, TM6SF2, GCKR, and MBOAT7.

20. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
NAFLD
Fat supply exceeds
adipose storage
capacity
Neuschwander-Tetri. Hepatology. 2010;52:774.

21. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
NAFLD
Fat supply exceeds
adipose storage
capacity
Genetic
contributors
Dietary/
environmental
contributors
Neuschwander-Tetri. Hepatology. 2010;52:774.

22. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
NAFLD
Fat supply exceeds
adipose storage
capacity
Insulin
resistance
?
Neuschwander-Tetri. Hepatology. 2010;52:774. Cohen. Science.
2011;332:1519. Chakravarthy. Endocrinol Diabetes Metab. 2020;3:e00112.

23. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
NAFLD
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
Insulin
resistance
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
??
Neuschwander-Tetri. Hepatology.
2010;52:774. Cohen. Science.
2011;332:1519. Chakravarthy.
Endocrinol Diabetes Metab.
2020;3:e00112. Yen. J Clin Med.
2022;11:1445.

24. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
NAFLD
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
Insulin
resistance
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
Controversial, but:
• Data show correlations,
not causation
• Variants of ApoB, PNPLA3
associated with NAFLD
but not IR1,2
1. Neuschwander-Tetri. Hepatology. 2010;52:774.
2. Cohen. Science. 2011;332:1519.

25. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
NAFLD
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
Insulin
resistance
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
1. Neuschwander-Tetri. Hepatology. 2010;52:774.
2. Cohen. Science. 2011;332:1519.

26. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
Insulin
resistance
Increased
circulating
FFA
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
NAFLD
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
Neuschwander-Tetri.
Hepatology.
2010;52:774.
Cohen. Science.
2011;332:1519.
Chakravarthy.
Endocrinol Diabetes
Metab.
2020;3:e00112.
Yen. J Clin Med.
2022;11:1445.

27. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
Insulin
resistance
Increased
circulating
FFA
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
NAFLD
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
Rx
Rx
Rx
Rx
Rx
Rx
Neuschwander-Tetri.
Hepatology.
2010;52:774.
Cohen. Science.
2011;332:1519.
Chakravarthy.
Endocrinol Diabetes
Metab.
2020;3:e00112.
Yen. J Clin Med.
2022;11:1445.

28. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
Insulin
resistance
Increased
circulating
FFA
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
NAFLD
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
Ideal
metabolic
Rx?
Neuschwander-Tetri. Hepatology.
2010;52:774. Cohen. Science.
2011;332:1519. Chakravarthy.
Endocrinol Diabetes Metab.
2020;3:e00112. Yen. J Clin Med.
2022;11:1445.

29. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Role of Metabolic Comorbidities
Insulin
resistance
Increased
circulating
FFA
Fat supply exceeds
adipose storage
capacity
Hypertension
Hyperuricemia
Dyslipidemia
NAFLD
Hyperglycemia
Macrovascular
disease
Type 2 diabetes
Neuschwander-Tetri. Hepatology.
2010;52:774. Cohen. Science.
2011;332:1519. Chakravarthy.
Endocrinol Diabetes Metab.
2020;3:e00112. Yen. J Clin Med.
2022;11:1445.

30. Slide credit: clinicaleducationalliance.com
The Pathogenic Relationship
Between Diabetes and NASH
Gastaldelli. JHEP Rep. 2019;1:312.
Impaired
Activation
Adipose Tissue Insulin Resistance
Insulin resistance in liver and muscle
Activation of proinflammatory pathways
Impaired insulin secretion
↓ Anti-inflammatory
adipokine secretion
↓ Adiponectin, IL-1
↑ Lipolysis
FFA
Lipotoxicity
↑ Secretion of
proinflammatory cytokines
MCP-1, TNF-α
TGFβ, IL-6, leptin

31. Slide credit: clinicaleducationalliance.com
Role of GLP-1 in NASH Pathogenesis
Armstrong. Clinical Liver Disease. 2017;10:32.
Brain
↑ Neuroprotection
↑ Memory
↓ Appetite
Liver
↑ Glucose production
Muscle
↑ Glucose uptake
↑ Glucose storage
Heart
↑ Myocardial contractility
↑ Heart rate
↑ Myocardial injury secondary to ischemia
Stomach
↓ Gastric emptying
↓ Gastric acid secretion
Pancreas
↑ Insulin secretion
↓ Glucagon secretion
↑ Insulin biosynthesis
↑ New β-cell formation
↓ β-cell apoptosis
↑ Insulin
Sensitivity

32. Slide credit: clinicaleducationalliance.com
NASH Pathogenesis: Summary
 Epidemiologic data have been interpreted to
suggest complex bidirectional relationships
 Mechanistic data indicate common underlying causes
‒ Adipose tissue overwhelmed for fat storage
‒ Insulin resistance
‒ Genetic contributions that predispose to NAFLD/NASH that are additive to
insulin resistance/adipose dysfunction
 Therapies that address underlying metabolic disease may be effective
‒ Treatments focused on inflammation/death pathways have not worked
?
Metabolic disease/IR
NASH
Type 2 diabetes
NASH
Type 2 diabetes
Tomah. Clin Diabetes Endocrinol. 2020;6:9. Neuschwander-Tetri. Hepatology. 2010;52:774. Cohen. Science. 2011;332:1519.
Chakravarthy. Endocrinol Diabetes Metab. 2020;3:e00112. Ferguson. Nat Rev Endocrinol. 2021;17:484.

33. www.clinicaloptions.com/internal-medicine
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