"CERAMIDE"

BIOCHEMISTRY
Lecturer: Prof. Dr. Leny Yuanita, M.Kes.

Created by:
Era Melania / 18030194085 / PKU 2018

CHEMISTRY DEPARTMENT
FACULTY OF MATHEMATICS AND NATURAL SCIENCE
SURABAYA STATE UNIVERSITY
2020
 TABLE OF CONTENT

CHAPTER I PRELIMINARY ...................................................................................... 3

1.1 Background .................................................................................................... 3
1.2 Problem Formulation ...................................................................................... 4
1.3 Purpose ........................................................................................................... 4
CHAPTER II CONTENT ............................................................................................. 5
2.1 Introduction .................................................................................................... 5
2.2 Ceramides in Insulin Resistance ..................................................................... 6
2.3 Ceramides and Inflammation ......................................................................... 9
2.4 Role of Ceramides in the Skin Barrier and Skin Disorders .......................... 11
2.5 Ceramides and Dyslipidemia........................................................................ 12
2.6 Topical Applications of Ceramides .............................................................. 14
2.7 Roles of Ceramide in Distinct Pathways of Cell Regulation ....................... 16
2.8 Function of Ceramide as a Biostat ............................................................... 18
CHAPTER III CONCLUSION ................................................................................... 20
REFERENCES............................................................................................................ 21

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 CHAPTER I
PRELIMINARY

1.1 Background
Ceramides belong to the second group of sphingosine-based lipid
messengers molecules involved in the regulation of various cellular responses
to exogenous stimuli. Ceramide is a substance from the Phytosphingosine
group that is naturally present around the stratum corneum area in our skin,
has skin moisturizing activity. As the process of aging occurs, the ceramides
will decrease in number, bringing dryness to the skin.
Ceramide is a component epidermal lipids that are naturally present in
the skin around the stratum corneum which has an effect as a guard skin
moisture by binding, balance and have the ability to hold water on the skin.
Ceramide on the skin will naturally decrease over time with aging and other
factors being impact on dry skin. Ceramide can be given deal with skin
dryness through improved skin barrier function.
Ceramide (a molecule water retaining in the extracellular space in
stratum corneum and ceramide bundles with a structural matrix protein which
forms the defense function). Thing it causes skin barrier function disturbed
which resulted in increased fluid loss through skin, resulting in drier skin and
sensitive to various influences physical and chemical.
Ceramide acts as a second messenger to regulate various cellular
functions. For example, increased ceramide levels caused by stress
stimulation can lead to apoptosis. Ceramide can interact with intracellular
target proteins or create a membrane platform enriched with ceramide, which
clumps receptors to activate signaling pathways. Because ceramide has the
potential to affect various internals mechanism, changes in the concentration
of ceramide in plasma and tissue can lead to lipotoxicity, resulting in several
diseases including neurodegenerative disorders, cancer and MetS. To increase

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 evidence also suggests the relevance of ceramide acyl chain lengths in the
pathogenesis of such diseases.

1.2 Problem Formulation

1. What is the definition of ceramide?
2. What are the role of ceramide in life?

1.3 Purpose
1. To know the definition of ceramide?
2. To know the role of ceramide in life?

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 CHAPTER II
CONTENT

2.1 Introduction
Ceramides, a class of sphingolipids, consist of a sphingosine backbone
attached to fatty acids part through amide bonds. Meanwhile, Ceramide levels
in human plasma sphingolipids only 2.8% (Hammad et al., 2010).
Considering the chemical structure of ceramides, they are highly
lipophilic compounds because the ratio of long-chain fatty acids to the
hydrophilic head part is high. As such, ceramides are poorly water-soluble
compounds. Also, ceramides are compounds with high molecular weight.
Ceramides are the central molecules in sphingolipid metabolism.
There are three Ceramide lines generation including de novo synthesis,
hydrolytic pathway and rescue line. (i) The de novo synthesis of Cer begins
with the condensation of serine and palmitoyl-CoA to produce 3-
ketosphinganine via the enzyme serine palmitoyltransferase (SPT) in the
endoplasmic reticulum (ER) (ii) In the hydrolytic pathway, Cer is synthesized
via the hydrolysis of sphingomyelin and complex sphingolipids (iii) The
salvage pathway is the synthesis of Cer from sphingosine (Walchuk et al.,
2020).
Our skin consists of two main layers, namely the dermis and epidermis
and has many functions such as a barrier to the outside world. This helps
regulate temperature, keeps germs and irritants away and helps keep moisture
from entering. In the epidermis there are five layers. The outermost layer
called the stratum corneum is composed of cells and a fat-like material called
lipids. Elias describes this layer as brick and mortar: brick becomes cells and
mortar becomes lipid. The intercellular lipids consist of 40% ceramide, 25%
cholesterol, 25% free fatty acids and 10% cholesteryl sulfate. Ceramides have
been found to be the most important components in the stratum corneum for
maintaining barrier function.

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 Up to nine different ceramides have been identified in the skin and in
the ceramides there are two types: Sphingosine and Phytosphingosine. The
type of ceramide and its structure determine the function of the ceramides, but
their overall function is to help maintain water retention in the stratum
corneum. Many things can drain skin moisture such as detergents or bad
weather. This can rob the skin of the lipids it needs to help maintain a healthy
barrier. Damaged or exhausted barriers can cause irritation, increased skin
sensitivity and skin dryness. Because ceramides are a major component of
intercellular lipids and contribute to water retention of the skin, they are
important for long-term relief of dryness and decreased skin sensitivity.
Ceramides can be incorporated into skin care products because of their
moisturizing properties.
The acyl chain length of ceramide varies between 14 to 30 carbons,
consisting of mainly SFA or monounsaturated fatty acids (MUFA). In general,
C18:0-Cer is the most abundant specie in the brain, while C24:0- and C24:1-
Cer are abundant in other tissues including liver, muscle, heart and plasma,
indicating their tissue specificity and distinct functional roles.

2.2 Ceramides in Insulin Resistance

Resistance to insulin is a pathophysiological state related to the
decreased response of peripheral tissues to the insulin action,
hyperinsulinemia and raised blood glucose levels caused by increased hepatic
glucose outflow. All the above precede the onset of full-blown type 2
diabetes. According to the World Health Organization (WHO), in 2016 more
than 1.9 billion people over 18 years of age were overweight and about 600
million were obese. Currently, the primary hypothesis explaining the
probability of occurrence of insulin resistance assigns a fundamental role of
lipids accumulation in adipocytes or nonadipose tissue (muscle, liver) and the
locally developing chronic inflammation caused by adipocytes hypertrophy.
However, the major molecular pathways are unknown.

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 That sphingolipid ceramide is the main culprit that combines a large
number of nutrients (for example, saturated fatty acids) and inflammatory
cytokines (eg TNFα) for insulin development resistance. Accumulation of
sphingolipid ceramide in obese human tissue, Western diets of mice and non
human primates are in line with diabetes, hypertension, heart failure or
atherosclerosis. In hypertrophic adipose tissue, after which adipocytes are
superior their storage capacity, neutral lipids begin to accumulate in the
nonadipose tissue, causing organ dysfunction. Furthermore, obesity is closely
related to the development of chronic disease inflammation and direct release
of cytokines from adipocytes or from macrophages which infiltrated the
adipose tissue. Enzymes that play a role in ceramide metabolism are very
potential therapeutic targets for manipulating the sphingolipid content in
tissues, either by means of inhibition their synthesis or through stimulation of
ceramide degradation. In this review, we are will evaluate the mechanisms
responsible for the development of insulin resistance and a possible
therapeutic perspective.
Obesity is the most common trigger for insulin development resistance
to the skeletal muscles and liver. Both are integral to the metabolic syndrome
along with glucose intolerance, hypertriglyceridemia, low HDL cholesterol,
hypertension, atherosclerosis, and impaired fibrinolytic capacity (Gupta &
Gupta, 2010).
Insulin resistance occurs in almost 20–25% of the human population
and is defined as a decreased response of the peripheral tissues to insulin
action, and consequently impairment in postprandial nutrient storage mainly
in skeletal muscle and in the liver. At this stage, pancreatic islets are not yet
damaged and respond to elevated blood glucose levels by insulin
oversecretion, resulting in their hypertrophy and necrosis (Saltiel, 2001).
On the other hand, as a continuous consequence maintain high
concentrations of insulin, peripheral tissue become resistant to this hormone.
Insulin resistance and weight gain is a non-alcoholic, stroke-causing factor

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Fatty liver disease (NAFLD), asthma, cancer, polycystic ovaries syndrome,
Alzheimer's disease, hypertension or atherosclerosis. The insulin signaling
system is complex and various. However, the genetic approach provides
valuable value insight into certain early forms of diabetes but failed to clarify
insulin resistance. Ceramides, reactive oxygen species, diacylglycerol,
branched chain amino acids, short chain acylcarnitines, and other metabolites
have all been implicated as insulin action antagonists. Here we will review the
suggestions mechanisms responsible for the onset of insulin resistance and
perspectives for the treatment of patients at risk of diabetes.
Accumulation intramuscular lipid accumulation, in particular:
diacylglycerols (DAG), ceramide (Cer) and long-chain acylCoA (LCACoA)
(15-18) (which are novo synthesis of both ceramide and DAG) was proposed
involved in the induction of insulin resistance. Bioactive sphingolipids such as
ceramide, sphingosine (Sph), and sphingosine 1-phosphate (S1P) combines
excess nutrition, inflammation, and nutrition metabolic dysregulation (Kang et
al., 2013).
Ceramides are important bioactive lipids included in the sphingolipid
family is produced from fatty acids and sphingosine or by sphingomyelin
hydrolysis. Ceramides in Biological membrane is part of the membrane
microdomain, known as lipid rafts, which stabilize the structure of cell
membranes and modulate the distribution of receptors and signaling
molecules. ceramides affect cell signaling pathways that mediate growth,
proliferation, motility, adhesion, differentiation, aging, stopping growth,
apoptosis.
The rate of ceramides generation depends mainly on the availability of
long-chain saturated fatty acids, which participate in the novo ceramide
synthesis within the endoplasmic reticulum. The rate of ceramides generation
depends mainly on the availability of long-chain saturated fatty acids, which
participate in the novo ceramide synthesis within the endoplasmic reticulum.
Ceramides vary in acyl-chain lengths from C14:0 to C30:0. At the first, rate-

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 limiting step of the de novo pathway, serine palmitoyltransferase (SPT)
initiates the condensation of serine and palmitoyl-CoA to produce 3-
ketosphinganine. Further reactions lead to the formation of sphinganine which
is acylated to dihydroceramide by six ceramide synthase enzymes (CerS1– 6),
and then to ceramide through dehydroceremide desaturase.
The rate of ceramides generation depends mainly on the availability of
long-chain saturated fatty acids, which participate in the novo ceramide
synthesis within the endoplasmic reticulum (48). Ceramides vary in acyl-
chain lengths from C14:0 to C30:0. At the first, rate-limiting step of the de
novo pathway, serine palmitoyltransferase (SPT) initiates the condensation of
serine and palmitoyl-CoA to produce 3-ketosphinganine. Further reactions
lead to the formation of sphinganine which is acylated to dihydroceramide by
six ceramide synthase enzymes (CerS1– 6), and then to ceramide through
dehydroceremide desaturase.

2.3 Ceramides and Inflammation

Inflammation is the body's natural immune response to infection or
tissue injury. Whereas in chronic conditions, there is often consistent low
grade inflammation. Form of systemic inflammation and continuous low-level
activation of the immune system as evidenced by a slight increase in
inflammatory mediators over a long period of time.
Accumulating evidence suggests that ceramide 1-phosphate has anti-
inflammatory properties under certain circumstances, or that it can
specifically induce pro-inflammatory or anti-inflammatory responses
depending on cell type. Initial studies showed that ceramide 1-phosphate
potently inhibited the accumulation of A-SMase-derived ceramides in primary
bone marrow-derived macrophages (Gomez-Munoz et al., 2004).
Although in that study the inhibition of A-SMase was related to the
prosurvival properties of ceramide 1-phosphate, this enzyme may also be
associated to inflammatory responses. In fact, upregulation of ASMase and

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ceramide formation were shown to play important roles in PAF-mediated
pulmonary edema, and internalization of bacteria into lung epithelial cells
thereby favoring infection (Goggel et al., 2004).
Of interest, in addition to its role in inflammation, A-SMase was
recently implicated in tumor lung metastasis. Specifically, intravenous
injection of melanoma cells into wild type mice resulted in multiple lung
metastases, while ASMase deficient mice were protected from pulmonary
tumor spread. Therefore, inhibition of A-SMase and the subsequent depletion
of ceramide levels by ceramide 1-phosphate may be essential for resolution of
inflammation and infection in the lung, and may also be important for
decreasing pulmonary tumor dissemination. In this connection, we have
recently shown that ceramide 1-phosphate potently inhibits cigarette smoke-
induced airway inflammation.
Specifically, ceramide 1-phosphate was able to counteract the
proinflammatory effects elicited by ceramides, which triggered apoptosis of
pulmonary epithelial cells leading to emphysema. C1P inhibited both acute
and chronic inflammation, and attenuated the development of emphysema
potently in a mouse model of chronic obstructive pulmonary disease (COPD).
These actions were associated to inhibition of the activity and expression of
N-SMase, NF-κB, and the pro-inflammatory cytokines TNF-α, IL-1β, IL-6,
keratinocyte chemoattractant (KC) and macrophage inflammatory protein-2
(MIP-2) in mice lungs and human airway epithelial cells and neutrophils
(Baudiss et al., 2015).
The antiinflammatory properties of ceramide 1-phosphate are
highlighted by recent reports showing that ceramide 1-phosphate potently
inhibited the production of TNF-α that was stimulated by lipopolysaccharide
(LPS) and by work from Kester and co-workers showing that in human
embryonic kidney cells (HEK 293) stably transfected with human toll-like
receptor-4 (TLR4), CD14, and MD-2, exogenously added ceramide 1-
phosphate decreased LPS-activated transcription of NF-κB. The functional

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 consequence of ceramide 1-phosphate inhibition of this transcription factor
was a reduction in LPS-mediated cytokine release from HEK 293 TLR4-
expressing cells as well as from human peripheral blood mononuclear cells.
Specifically, ceramide 1-phosphate abrogated the production of IL-6, IL-8 and
IL-1β, thereby indicating that exogenous ceramide 1-phosphate may function
as an anti-inflammatory lipid mediator of some immune responses.

2.4 Role of Ceramides in the Skin Barrier and Skin Disorders

The morphology of ceramide holding the corneocytes and attaining to
intercellular matrix knits the skin and remain the skin integrity. The ordered
alignment of lipid forms a closed system to prevent transepidermal water loss
(TEWL) and makes the stratum corneum more impermeable. As a result,
changes in the amount and organization of the stratum corneum ceramides
cause skin disorders with barrier defects.
Atopic dermatitis is a dermatological disorder characterized by dry
skin, pruritus, increased TEWL, and decreased skin barrier function.
Ceramide I, long-chain ceramides, decreased 52% in atopic dermatitis. In
addition, ceramide V in the non-lesion area of the skin was removed, and
ceramide I and ceramide III were reduced in the area of the lesion (Matsumoto
et al., 1999). In addition, metabolic pathways such as ceramidase are
overactive in the epidermis with atopic dermatitis.
Ichthyosis as much as atopic dermatitis, free fatty acid ratio reduces in
contradistinction for ceramides ratio. Also, orthorhombic organization and
long periodicity phase (LPP), having crucial roles in the skin barrier function,
degenerate inichthyosis patients.
Psoriasis In another skin disorder in which barrier defects occurs,
revealed the relation between ceramide composition and TEWL in psoriatic
and healthy skin. According to results, ceramide I, III, IV, V, and VI reduced
TEWL increased in all psoriatic scales.

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 Acne It is considered that altered ceramide values is also effective on
acne. Because of high-level TEWL in acne, altered ceramide could have a role
in this point. The correlation between them. However, TEWL is not negatively
correlated with symptoms even though all subclasses of ceramide are negatively
correlated with TEWL. Therefore, they considered the ceramide composition
of healthy skin and skin with acne according to season. As a result, decreased
ceramide aggravates the symptoms, especially in winter months. Seasonal
changes in the amount of ceramide are exposed by increasing TEWL. On the
other hand, healthy skin has high-level ceramide VI and VIII providing
adaptation of environmental conditions in winter months.
Gaucher Disease as a genetic disorder, Gaucher disease arising from β-
glucocerebrosidase enzyme deficiency is also related to the ceramide
biosynthesis and metabolism pathway. On glucosylceramide breaking down
to glucose and ceramide, β-glucocerebrosidase has a role with hydrolyzation.
After this stage, glucosylceramide is diminished and a ceramide molecule is
exposed. However, in patients with Gaucher disease, this metabolism pathway
loses the function because of β-glucocerebrosidase deficiency. Unlike the
aforementioned disorders, a decrease in the amount of ceramide in Gaucher
disease is originated from this point.
Dry Skin, the lipid envelope, LPP, and orthorhombic organization keep
the moisturizing balance under control and reduce TEWL. In this way, even
though the skin is not moisturized by supplementary products, hydration
content is preserved in skin layers. With decreasing ceramide levels in the
skin, the barrier function of lipid envelopes becomes incapacitated. Compared
to dry and normal skin, ceramide I, II, III, IV, V and VI diminish with dryness,
while ceramides are at a high level in normal skin.

2.5 Ceramides and Dyslipidemia

Dyslipidemia is the pathological imbalance of circulating lipids
associated with increases in total cholesterol (TC), TAG and low-density

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lipoprotein cholesterol (LDL-C), often with accompanied reductions in HDL-
C. Increases in both plasma ceramide concentrations and hyperlipidemia
commonly occur in unison in both obese animals and humans (Iqbal et al.,
2017).
Approximately 98% of circulating ceramide are bound to lipoprotein
subfractions and are equally distributed on very low-density lipoproteins
(VLDL), LDL-C and HDL-C. Common species of Cer including C16:0-,
C22:0-, C24:0-, C24:1-Cer tend to be evenly distributed among these
lipoproteins, and circulating lipoprotein-bound ceramide is found to differ
among lean, obese and obese type 2 diabetic individuals (Boon et al., 2013).
Total circulating ceramide concentrations were elevated among obese
individuals with and without diabetes. No differences in VLDL-Cer among
groups was reported, however HDL-Cer was elevated in obese individuals
without diabetes, whereas LDL-Cer was significantly elevated among obese
diabetics. As LDL-Cer was positively correlated with HOMA-IR, it is likely
LDL-Cer plays a role in the pathogenesis of ceramide induced IR.
Traditionally, dyslipidemia has been considered a major risk factor for the
development of CVD. Recently, the increase in circulating ceramide
concentrations can be considered as a new predictor for CVD development. In
coronary artery disease patients, plasma Cer was predictive of coronary death
following adjustment for traditional CVD predictors including LDL-C,
HDLC, TC, TAGs, and C-reactive protein.
Consistent with research regarding IR and inflammation, distinct long-
chain ceramide species differ in their ability to predict cardiovascular death.
While long chain ceramide such as C16:0- and C18:0-Cer are associated with
an increased risk, very long chain ceramide species C22:0- and C24:0-Cer
may be less harmful or associated with lower risk of cardiovascular death It is
suggested that ceramide increases atherogenesis by promoting LDL
infiltration into the vessel wall, endothelial dysfunction and by increasing.

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 inflammation however, considering the differences among ceramide species,
there are likely numerous mechanisms involved.

2.6 Topical Applications of Ceramides

Decreased levels of stratum corneum ceramides have been shown to
be a major effect of the occurrence of skin disorders. As a result of this, the
researchers have thought that these disorders could be improved by replacing
decreased CERs levels. Therefore, topical applications including conventional
and novel carrier systems have been formulated by diverse researchers.
a. Conventional Carrier System
Several commercial lotions, creams, and moisturizers (e.g., Eucerin
Smoothing Repair Dry Skin Lotion, Eucerin Eczema Relief Body
Creme, CeraVe Moisturizing Lotion, CeraVe Suncare Sunscreen Face
SPF 30) based on ceramides 1 and 3 have been formulated in the
market. However, there is confusion regarding the permeability of the
skin and the efficacy of ceramides after topical application via
conventional carrier systems. The phytosphingosine, ceramide I,
ceramide III and ceramide VI-II in a simplified cream have a crucial
role in the hydration of skin and reducing TEWL values compared to
placebo data (Spada et al., 2018).
Ceramides in their conventional formulations could be efficient
to restore the skin barrier in skin disorders. However, glycyrrhetinic
acid (an anti-inflammatory compound) and ethoxydiglycol (a
penetration enhancer) were used to improve therapeutic efficacy and
skin permeation of ceramides in these studies, respectively. Hence,
these results also could be due to the aforementioned constituents
because emulsion including ceramide, niacin, and arginine-sodium-
PCA complex could not create a notable clinical response.
Aoki at al observed in the fluorescent light after 12 hours
following application that ceramide 2 NBD in emulsion formulating

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 with water, Tween 20 and octyldodecanol was able to permeate to all
layers of dry skin while remaining in the upper layer of healthy skin.
The researchers considered the relationship between the amounts of
endogenous ceramide in healthy/dry skin and penetration capability. It
is clear that dry skin consisting of low endogenous ceramide is
convenient for exogenous ceramide passing. The emulsions containing
ceramide I, ceramide IX-S and ceramide IX-L in ratio 0.3%,
cholesterol, 1,3 butylene glycol and aqueous lecithin were able to
restore the damaged LPP formation of stratum corneum lipids.
b. Novel Carrier Systems
Conventional carrier systems have been used for the delivery
of various skin compounds for many years. However, this system is
not suitable for delivery of skins with large molecular structures and
highly lipophilic compounds, due to the complex nature of the skin.
Therefore, researchers have developed new carrier systems such as
vesicular systems, microemulsions, and nanoparticles to overcome this
drawback.
Considering the literature review, the microemulsion
formulations are the most permeable preparations for topical
application of CERs among other novel carrier systems. This situation
could be based on directly improving penetration through the stratum
corneum due to the high surfactant content of formulations and
indirectly increasing solubility (thereby thermodynamic activity) of
CERs via microemulsions. Moreover, some researchers have suggested
that droplet size of microemulsions and nanoemulsions including
CERs is crucial for their penetration through the stratum corneum.
The relationship of droplet size and temperature change in the
production of o/w nanoemulsions. Another group showed that the type
of oil phase affects the droplet size of the nanoemulsion ceramide 3b.
In the study, the largest droplet size occurred in formulations with

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 avocado oil/oleic acid, while the smallest droplet sizes were obtained
in formulations with squalene.
In the literature, another option is ceramide-based liposomes
with high membrane fluidity, high fusion activity, and comprising
stratum corneum lipids to facilitate the penetration of ceramides to the
skin. These liposomes were composed of C-8
ceramide/cholesterol/linolenic acid/cholesterol sulfate = 45/5/5/45
(w/w%). Also, a human-type nanoceramide dispersion called Astalift
Jelly Aquarysta was developed to improve ceramide localization in the
stratum corneum. According to the results of in vivo tape stripping
studies, the localization of human-type nano ceramides in the stratum
corneum was determined to be 9 times greater than that of its
reference.
Apart from microemulsions, nanoemulsions, and liposomes,
new carrier systems for topical delivery of ceramides are nanoparticles
and microparticles. This system aims to control and target ceramide
delivery via nanoparticles. The penetration percentage of nanoparticles
was 60% while the microemulsion was 92% (Tessema et al., 2018).

2.7 Roles of Ceramide in Distinct Pathways of Cell Regulation

Recent discoveries have provided support to the principle that cells
have intrinsic biochemical and molecular machinery that functions primarily
to perceive various shapes injury and humiliation and to do accordingly
response program. Mammalian cells respond primarily to these stimuli by
undergoing cell cycle arrest to allow adequate time for repair of damage or by
undergoing apoptosis (programmed cell death) if the damage is too severe and
irreparable. That is, too it is likely that other outcomes, such as terminal cell
differentiation and aging, represent some form of stress response.
Some evidence suggests a role for ceramides in various forms to
suppress cell growth and death. First, the spectrum the causes of accumulation

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of ceramides include, and may be limited to, a large proportion the main cause
of apoptosis, terminal differentiation, or growth suppression. Growth factors
do not appear to produce a similar result response. Second, changes in
intracellular ceramide concentration in response these extracellular agents
precede the cellular effect of this agent on growth emphasis. Third, cell
treatment with cell-permeable analogs of ceramide such as C2- and C6-
ceramide has been shown to induce apoptosis, cell senescence, terminal
differentiation, or cell cycle arrest in several cell types.
This exogenous ceramide effect is specific to D-erythroceramide; D-
erythro-dihydroceramide does not have such activity. Dihydroceramide is a
naturally occurring ceramide which does not have 4-5 trans double bonds but
maintains the stereochemical configuration of D-erythroceramide, and its
absorption and metabolism are very similar to that of D-erythro-ceramide.
Ceramide, suppression of growth, and termination of the cell cycle. In
some cell lines, ceramides and causes the formation of ceramides inhibition of
thymidine uptake and induce a Go/G, termination of the cell cycle
accompanied by early dephosphorylation of the retinoblastoma gene product
(Rb). Some evidence shows a important role for Rb in mediating the cell cycle
capture in response to ceramides. Cells lacking Rb (such as the cell line that is
derived from retinoblastoma) shows no cells a stop cycle in response to
ceramides.
Cell which responds to ceramides becomes unresponsive when Rb is
deactivated or isolated by one of several Rb-binding proteins like the
adenoviral Ela and the big T SV40. On the other hand, the absence of Rb does
not seem to reduce responsiveness cells with apoptotic ceramide effect.
Ceramide free path to Rb regulations also exist. Ceramide-activated protein
kinase (CAPK). CAPK is a kinase associated with a membrane the specificity
of the substrate for serine or threonine near proline. In vitro, ceramide does
not activate this kinase in a partially purified preparation, which raises the
possibility that this kinase is not directly regulated by ceramide.

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2.8 Function of Ceramide as a Biostat
Unlike adenosine 3',5'-monophosphate (cyclic AMP), IP3,
phosphatidylinositol-3,4,5- trisphosphate (PIP3), and many eicosanoids,
ceramides and DAG do not work only in signal transduction. They are
important components in the intermediate metabolism of sphingolipids and
glycerophospholipids. Also, the changes that stand out the most in the amount
of ceramide and DAG occurs for a longer period of time than it seems with
cyclic AMP, IP3, or PIP3. Therefore, ceramides can function more as a
component of "biostats" that measure and initiate responses to cell stress, such
as the thermostat measures and regulates temperature.
For example, cellular concentration ceramides are increased by
systemic stress (such as those caused by TNF) or cell injury (such as such as
from heat or chemotherapy agents). The cell then responds to this change with
undergo apoptosis or stop growth. The concept of lipid biostats also offers a
solution to the paradoxical dual function of ceramides and DAG as
intermediate metabolites and second messengers and bioefector molecules.
Lots of enzymes able to regulate ceramide concentration via different
metabolic pathways and this individual enzyme maybe activated by different
pressures or extracellular agents. This enzyme can then function to integrate
the effects of multiple stimuli as a consequence of ceramide regulation
concentration. The ceramide concentration will then reflect the effects of
some of the stimuli and will serve as a gauge the overall amount of stress or
injury whose cell has opened.
Studies on the regulation and function of ceramides, and a more
general study of apoptosis and growth emphasis, begin determine the
regulated path in the end serves to handle systemic as well stress and cellular
injury it can cause cell cycle arrest, terminal differentiation, aging, or
apoptosis. Additional tools, such as specific enzyme inhibitors generation of
ceramides, is needed to strengthen the hypothesis raised here. An

18
understanding of this pathway can provide a the basis for developing therapies
to control cancer and inflammation.

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 CHAPTER III
CONCLUSION

Based on the literature study, we can conclude that:

1. Ceramide is a class of sphingolipids, consist of a sphingosine backbone attached
to fatty acids part through amide bonds.
2. The role of ceremide in life are:
 Ceramides in Insulin Resistance.
 Ceramides and Inflammation.
 Ceramides in the Skin Barrier and Skin Disorders.
 Ceramides and Dyslipidemia.
 Topical Applications of Ceramides.
 Roles of Ceramide in Distinct Pathways of Cell Regulation.
 Function of Ceramide as a Biostat.

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